Compounds and uses thereof

ABSTRACT

The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancers and viral infections.

BACKGROUND

Disorders can be affected by the BAF complex. BRD9 is a component of theBAF complex. The present invention relates to useful compositions andmethods for the treatment of BAF complex-related disorders, such ascancer and infection.

SUMMARY

Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9gene on chromosome 5. BRD9 is a component of the BAF (BRG1- orBRM-associated factors) complex, a SWI/SNF ATPase chromatin remodelingcomplex, and belongs to family IV of the bromodomain-containingproteins. BRD9 is present in several SWI/SNF ATPase chromatin remodelingcomplexes and is upregulated in multiple cancer cell lines. Accordingly,agents that reduce the levels and/or activity of BRD9 may provide newmethods for the treatment of disease and disorders, such as cancer andinfection. The inventors have found that depleting BRD9 in cells resultsin the depletion of the SS18-SSX fusion protein in those cells. TheSS18-SSX fusion protein has been detected in more than 95% of synovialsarcoma tumors and is often the only cytogenetic abnormality in synovialsarcoma. Additionally, evidence suggests that the BAF complex isinvolved in cellular antiviral activities. Thus, agents that degradeBRD9 (e.g., compounds) are useful in the treatment of disorders (e.g.,cancers or infections) related to BAF, BRD9, and/or SS18-SSX.

The present disclosure features compounds and methods useful fortreating BAF-related disorders (e.g., cancer or infection).

In an aspect, the disclosure features a compound having the structureFormula I:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is N or CH, and X² is C—R⁷; or X¹ is C—R⁷, and X² is N or CH;

R⁷ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedamino, optionally substituted sulfone, optionally substitutedsulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms;

X³ is N or CH;

X⁴ is N or CH;

G is optionally substituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉heteroaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, R¹ is H. In some embodiments, R¹ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R¹ is optionallysubstituted C₂-C₆ alkenyl. In some embodiments, R¹ is optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments. R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H or

In some embodiments, R¹ is H. In some embodiments, R¹ is

In some embodiments, Z¹ is CR². In some embodiments, Z¹ is N.

In some embodiments, R² is H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.

In some embodiments, R² is H, halogen, or optionally substituted C₁-C₆alkyl.

In some embodiments, R² is H, F, or

In some embodiments, R² is H. In some embodiments, R² is F. In someembodiments, R² is

In some embodiments, R⁷ is optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms. In someembodiments, R⁷ is optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted carbocyclyl having3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6atoms. In some embodiments, R⁷ is optionally substituted C₁-C₆ alkoxy oroptionally substituted amino. In some embodiments, R⁷ is optionallysubstituted sulfone or optionally substituted sulfonamide.

In some embodiments, R⁷ is optionally substituted C₁-C₆ alkyl oroptionally substituted carbocyclyl having 3 to 6 atoms. In someembodiments, R⁷ is optionally substituted C₁-C₆ heteroalkyl oroptionally substituted heterocyclyl having 3 to 6 atoms. In someembodiments, R⁷ is optionally substituted C₁-C₆ alkyl or optionallysubstituted C₁-C₆ heteroalkyl.

In some embodiments, R⁷ is optionally substituted C₁-C₆ alkyl. In someembodiments, R⁷ is optionally substituted C₁-C₆ heteroalkyl. In someembodiments, R⁷ is optionally substituted C₁-C₆ alkoxy.

In some embodiments, R⁷ is optionally substituted amino. In someembodiments, R⁷ is optionally substituted carbocyclyl having 3 to 6atoms. In some embodiments, R⁷ is optionally substituted heterocyclylhaving 3 to 6 atoms. In some embodiments, R⁷ is optionally substitutedsulfone. In some embodiments, R⁷ is optionally substituted sulfonamide.

In some embodiments, R⁷ is optionally substituted C₁-C₃ alkyl. In someembodiments, R⁷ is optionally substituted C₁-C₃ heteroalkyl.

In some embodiments, R⁷ is

In some embodiments, R⁷ is —NR³R⁴ or —OR⁴, where R³ is H or optionallysubstituted C₁-C₆ alkyl, and R⁴ is optionally substituted C₁-C₆ alkyl.

In some embodiments, R⁷ is —NR³R⁴. In some embodiments, R⁷ is —OR⁴.

In some embodiments, R³ is H. In some embodiments, R³ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, R³ is H and R⁴ is methyl. In some embodiments, R³is methyl and R⁴ is methyl.

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is optionally substituted carbocyclyl having 3to 6 atoms or optionally substituted heterocyclyl having 3 to 6 atoms.In some embodiments, R⁷ is optionally substituted carbocyclyl having 3to 6 atoms. In some embodiments, R⁷ is optionally substitutedheterocyclyl having 3 to 6 atoms.

In some embodiments, R⁷ is carbocyclyl having 3 to 6 atoms orheterocyclyl having 3 to 6 atoms. In some embodiments, R⁷ is carbocyclylhaving 3 to 6 atoms. In some embodiments, R⁷ is heterocyclyl having 3 to6 atoms.

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, X¹ is N and X² is C—R⁷. In some embodiments, X¹ isCH and X² is C—R⁷. In some embodiments, X¹ is C—R⁷ and X² is N. In someembodiments, X¹ is C—R⁷ and X² is CH.

In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴, C—OR⁴,

or X¹ is C—NR³R⁴, C—OR⁴,

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² isC—NR³R⁴,

or X¹ is C—NR³R⁴,

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH.

In some embodiments, R⁷ is —NR³R⁴, —OR⁴, or optionally substitutedheterocyclyl having 3 to 6 atoms.

In some embodiments, X¹ is N and X² is C—NR³R⁴. In some embodiments, X¹is C—NR³R⁴ and X² is N. In some embodiments, X¹ is N and X² is C—OR⁴. Insome embodiments, X¹ is C—OR⁴ and X² is N.

In some embodiments, R³ is H. In some embodiments, R³ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is methyl, ethyl,

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is methyl, ethyl,

In some embodiments, X³ is N. In some embodiments, X³ is CH.

In some embodiments, X⁴ is N. In some embodiments, X⁴ is CH.

In some embodiments, X³ is N and X⁴ is N.

In some embodiments, X³ is N and X⁴ is CH.

In some embodiments, X³ is CH and X⁴ is N.

In some embodiments, X³ is CH and X⁴ is CH.

In some embodiments, G is optionally substituted C₃-C₁₀ carbocyclyl oroptionally substituted C₂-C₉ heterocyclyl. In some embodiments, G isoptionally substituted C₆-C₁₀ aryl or optionally substituted C₂-C₉heteroaryl.

In some embodiments, G is optionally substituted C₃-C₁₀ carbocyclyl. Insome embodiments, G is optionally substituted C₆-C₁₀ aryl. In someembodiments, G is optionally substituted C₂-C₉ heterocyclyl. In someembodiments, G is optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G is

where

each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H,halogen, optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4)and R^(G5), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, R^(G1) is H; R^(G2) is

and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2) is

R^(G4) is H; and R^(G5) is

In some embodiments, R^(G1) is H; R^(G2) is

R^(G4) is Cl or F; and R^(G5) is H. In some embodiments, R^(G1) is H;R^(G2) is

R^(G4) is H; and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2)is

and R^(G5) is H.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl. In someembodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl or optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6) is H,

In some embodiments, R^(G6) is H or

In some embodiments, R^(G6) is H.

In some embodiments, R^(G1) is H, F,

In some embodiments, R^(G1) is H.

In some embodiments, R^(G2) is H, F,

In some embodiments, R^(G2) is H.

In some embodiments, R^(G3) is H, F

In some embodiments, R^(G3) is H.

In some embodiments, R^(G4) is H, F,

In some embodiments, R^(G4) is H.

In some embodiments, R^(G5) is H, F,

In some embodiments, R^(G5) is H.

In some embodiments, one or more of R^(G1), R^(G2), R^(G3), R^(G4), andR^(G5) is H. In some embodiments, two or more of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is H. In some embodiments, three or more of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is H. In some embodiments, each ofR^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is H.

In some embodiments, G is

where

each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is, independently,H, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/or R^(G10)and R^(G11), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/orR^(G10) and R^(G11), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, F, Cl,

In some embodiments, R^(G8) is

In some embodiments, G is

In some embodiments, R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.

In some embodiments, G is

where

each of R^(G12), R^(G13), and R^(G14) is, independently, H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G12), R^(G13), and R^(G14) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, the compound of Formula I has the structure ofFormula Ia:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ib:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ic:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Id:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ie:

where each of R⁵ and R⁶ is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, or optionally substituted C₂-C₉heterocyclyl; or R⁵ and R⁶, together with the nitrogen to which each isattached, combine to form an optionally substituted C₂-C₉ heterocyclyl,or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula If:

where each of R⁵ and R⁶ is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, or optionally substituted C₂-C₉heterocyclyl; or R⁵ and R⁶, together with the nitrogen to which each isattached, combine to form an optionally substituted C₂-C₉ heterocyclyl,or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ig:

where each of R⁵ and R⁶ is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, or optionally substituted C₂-C₉heterocyclyl; or R⁵ and R⁶, together with the nitrogen to which each isattached, combine to form an optionally substituted C₂-C₉ heterocyclyl,or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ih:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ij:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ik:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Im:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula In:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Io:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ip:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Iq:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I has the structure ofFormula Ir:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one ofcompounds B1-B6 in Table 1, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds B1-B3 and B6 in Table 1, or a pharmaceutically acceptablesalt thereof.

In an aspect, the disclosure features a compound having the structure ofany one of compounds B1-B6 in Table 1, or a pharmaceutically acceptablesalt thereof.

In an aspect, the disclosure features a compound having the structure ofany one of compounds B1-B3 and B6 in Table 1, or a pharmaceuticallyacceptable salt thereof.

In an aspect, the disclosure features a compound having the structure ofany one of compounds B4 and B5 in Table 1, or a pharmaceuticallyacceptable salt thereof.

TABLE 1 Compounds B1-B6 of the Disclosure Compound No. Structure B1

B2

B3

B4

B5

B6

In an aspect, the disclosure features a compound having the structure ofFormula II:

A-L-B  Formula II,

where

L is a linker;

B is a degradation moiety; and

A has the structure of Formula III:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is N or CH, and X² is C—R^(7″); or X¹ is C—R^(7″), and X² is N or CH;

R^(7″) is

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedamino, optionally substituted sulfone, optionally substitutedsulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms;

R^(7′) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl;

X³ is N or CH;

X⁴ is N or CH;

G″ is

optionally substituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉heteroaryl;

G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and

A¹ is a bond between A and the linker,

where G″ is

or R^(7″) is

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, R¹ is H. In some embodiments, R¹ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R¹ is optionallysubstituted C₂-C₆ alkenyl. In some embodiments, R¹ is optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H or

In some embodiments, R¹ is H. In some embodiments, R¹ is

In some embodiments, Z¹ is CR². In some embodiments, Z¹ is N.

In some embodiments, R² is H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.

In some embodiments, R² is H, halogen, or optionally substituted C₁-C₆alkyl.

In some embodiments, R² is H, F, or

In some embodiments, R² is H. In some embodiments, R² is F. In someembodiments, R² is

In some embodiments, R^(7″) is optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms. In someembodiments, R^(7″) is optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted carbocyclyl having3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6atoms. In some embodiments, R^(7″) is optionally substituted C₁-C₆alkoxy or optionally substituted amino. In some embodiments, R^(7″) isoptionally substituted sulfone or optionally substituted sulfonamide.

In some embodiments, R^(7″) is optionally substituted C₁-C₆ alkyl oroptionally substituted carbocyclyl having 3 to 6 atoms. In someembodiments, R^(7″) is optionally substituted C₁-C₆ heteroalkyl oroptionally substituted heterocyclyl having 3 to 6 atoms. In someembodiments, R^(7″) is optionally substituted C₁-C₆ alkyl or optionallysubstituted C₁-C₆ heteroalkyl.

In some embodiments, R^(7″) is optionally substituted C₁-C₆ alkyl. Insome embodiments, R^(7″) is optionally substituted C₁-C₆ heteroalkyl. Insome embodiments, R^(7″) is optionally substituted C₁-C₆ alkoxy. In someembodiments, R^(7″) is optionally substituted amino. In someembodiments, R^(7″) is optionally substituted carbocyclyl having 3 to 6atoms. In some embodiments, R^(7″) is optionally substitutedheterocyclyl having 3 to 6 atoms. In some embodiments, R^(7″) isoptionally substituted sulfone. In some embodiments, R^(7″) isoptionally substituted sulfonamide.

In some embodiments, R^(7″) is optionally substituted C₁-C₃ alkyl. Insome embodiments, R^(7″) is optionally substituted C₁-C₃ heteroalkyl.

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is —NR³R⁴ or —OR⁴, where R³ is H oroptionally substituted C₁-C₆ alkyl, and R⁴ is optionally substitutedC₁-C₆ alkyl.

In some embodiments, R^(7″) is —NR³R⁴. In some embodiments, R^(7″) is—OR⁴.

In some embodiments, R³ is H. In some embodiments, R³ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, R³ is H and R⁴ is methyl. In some embodiments, R³is methyl and R⁴ is methyl.

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is optionally substituted carbocyclyl having3 to 6 atoms or optionally substituted heterocyclyl having 3 to 6 atoms.In some embodiments, R^(7″) is optionally substituted carbocyclyl having3 to 6 atoms. In some embodiments, R^(7″) is optionally substitutedheterocyclyl having 3 to 6 atoms.

In some embodiments, R^(7″) is carbocyclyl having 3 to 6 atoms orheterocyclyl having 3 to 6 atoms. In some embodiments, R^(7″) iscarbocyclyl having 3 to 6 atoms. In some embodiments, R^(7″) isheterocyclyl having 3 to 6 atoms.

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, R^(7″) is

In some embodiments, X¹ is N and X² is C—R^(7″). In some embodiments, X¹is CH and X² is C—R^(7″). In some embodiments, X¹ is C—R^(7″) and X² isN. In some embodiments, X¹ is C—R^(7″) and X² is CH.

In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴, C—OR⁴,

or X¹ is C—NR³R⁴, C—OR⁴,

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² isC—NR³R⁴,

or X¹ is C—NR³R⁴,

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH. In some embodiments, X¹ is N or CH, and X² is C—NR³R⁴or

or X¹ is C—NR³R⁴ or

and X² is N or CH.

In some embodiments, R^(7″) is —NR³R⁴, —OR⁴, or optionally substitutedheterocyclyl having 3 to 6 atoms.

In some embodiments, X¹ is N and X² is C—NR³R⁴. In some embodiments, X¹is C—NR³R⁴ and X² is N.

In some embodiments, R³ is H. In some embodiments, R³ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is methyl, ethyl,

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is methyl, ethyl,

In some embodiments, X³ is N. In some embodiments, X³ is CH.

In some embodiments, X⁴ is N. In some embodiments, X⁴ is CH.

In some embodiments, X³ is N and X⁴ is N.

In some embodiments, X³ is N and X⁴ is CH.

In some embodiments, X³ is CH and X⁴ is N.

In some embodiments, X³ is CH and X⁴ is CH.

In some embodiments, G″ is

In some embodiments, G′ is optionally substituted C₃-C₁₀ carbocyclyleneor optionally substituted C₂-C₉ heterocyclylene. In some embodiments, G′is optionally substituted C₆-C₁₀ arylene or optionally substituted C₂-C₉heteroarylene.

In some embodiments, G′ is optionally substituted C₃-C₁₀ carbocyclylene.In some embodiments, G′ is optionally substituted C₆-C₁₀ arylene. Insome embodiments, G′ is optionally substituted C₂-C₉ heterocyclylene. Insome embodiments, G′ is optionally substituted C₂-C₉ heteroarylene.

In some embodiments, G′ is

where

each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1′) and R^(G2′), R^(G2′) and R^(G3′), R^(G3′)and R^(G4′), and/or R^(G4′) and R^(G5′), together with the carbon atomsto which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) isA¹, or

is substituted with A¹.

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl,optionally substituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, oroptionally substituted amino; or R^(G1′) and R^(G2′), R^(G2′) andR^(G3′), R^(G3′) and R^(G4′), and/or R^(G4′) and R^(G5′), together withthe carbon atoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) isA¹, or

is substituted with A¹.

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1′) and R^(G2′), R^(G2′) and R^(G3′), R^(G3′) andR^(G4′), and/or R^(G4′) and R^(G5′), together with the carbon atoms towhich each is attached, combine to form

is optionally substituted C₂-C₉ heteroaryl or optionally substitutedC₂-C₉ heterocyclyl, any of which is optionally substituted with A¹,where one of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is A¹, or

is substituted with A¹.

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, F, Cl,

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, F,

In some embodiments, each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, F, Cl,

In some embodiments, R^(G3′) is A¹.

In some embodiments, R^(G1′) is H; R^(G2′) is

R^(G3′), is A¹; R^(G4′), is

and R^(G5′) is H. In some embodiments, R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is H; and R^(G5′) is

In some embodiments, R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is Cl or F; and R^(G5′) is H. In someembodiments, R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is H; and R^(G5′) is H. In some embodiments,R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is

and R^(G5′) is H.

In some embodiments, R^(G1′) and R^(G2′), R^(G2′) and R^(G3′), R^(G3′)and R^(G4′), and/or R^(G4′) and R^(G5′), together with the carbon atomsto which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A¹, where one of R^(G1′), R^(G2′), R^(G3′), R^(G4′),and R^(G5′) is A¹, or

is substituted with A¹. In some embodiments, R^(G1′) and R^(G2′),R^(G2′) and R^(G3′), R^(G3′) and R^(G4′), and/or R^(G4′) and R^(G5′),together with the carbon atoms to which each is attached, combine toform

is optionally substituted C₂-C₉ heteroaryl, which is optionallysubstituted with A¹, where one of R^(G1′), R^(G2′), R^(G3′), R^(G4′),and R^(G5′) is A¹, or

is substituted with A¹.

In some embodiments, G′ is

where R^(G6′) is H, A¹, or optionally substituted C₁-C₆ alkyl. In someembodiments, G′ is

where R^(G6′) is H, A¹, or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G1′) and R^(G2′), R^(G2′) and R^(G3′), R^(G3′)and R^(G4′), and/or R^(G4′) and R^(G5′), together with the carbon atomsto which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl or optionally substitutedC₂-C₉ heteroaryl, any of which is optionally substituted with A¹, whereone of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is A¹, or

is substituted with A¹.

In some embodiments, G′ is

where R^(G6′) is H, A¹, or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6′) is H, A¹,

In some embodiments, R^(G6′) is H, A¹, or

In some embodiments, R^(G6′) is H or A¹.

In some embodiments, R^(G6′) is H. In some embodiments, R^(G6′) is A¹.

In some embodiments, R^(G1′) is H, A¹, F,

In some embodiments, R^(G1′) is H.

In some embodiments, R^(G2′) is H, A¹, F,

In some embodiments, R^(G2′) is H.

In some embodiments, R^(G3′) is H, A¹, F,

In some embodiments, R^(G3′) is H.

In some embodiments, R^(G4′) is H, A¹, F,

In some embodiments, R^(G4′) is H.

In some embodiments, R^(G5′) is H, A¹, F,

In some embodiments, R^(G5′) is H.

In some embodiments, one or more of R^(G1′), R^(G2′), R^(G3′), R^(G4′),and R^(G5′) is H. In some embodiments, two or more of R^(G1′), R^(G2′),R^(G3′), R^(G4′), and R^(G5′) is H. In some embodiments, three or moreof R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is H.

In some embodiments, R^(G1′) is A¹. In some embodiments, R^(G2′) is A¹.In some embodiments, R^(G3′) is A¹. In some embodiments, R^(G4′) is A¹.In some embodiments, R^(G5′) is A¹. In some embodiments,

is substituted with A¹.

In some embodiments, G′ is

where

each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7′) and R^(G8′), R^(G8′) and R^(G9′), R^(G9′)and R^(G10′), and/or R^(G10′) and R^(G11′), together with the carbonatoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), andR^(G11′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl,optionally substituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, oroptionally substituted amino; or R^(G7′) and R^(G8′), R^(G8′) andR^(G9′), R^(G9′) and R^(G10′), and/or R^(G10′) and R^(G11′), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), andR^(G11′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7′) and R^(G8′), R^(G8′) and R^(G9′), R^(G9′) andR^(G10′), and/or R^(G10′) and R^(G11′), together with the carbon atomsto which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), andR^(G11′) is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), andR^(G11′) is, independently, H, A¹, F, Cl,

In some embodiments, R^(G8′) is

In some embodiments, G′ is

In some embodiments, R^(G7′) is H; R^(G8′) is

R^(G9′) is A¹; and R^(G11′) is H.

In some embodiments, G′ is

where

each of R^(G12′), R^(G13′), and R^(G14′) is, independently, H, A¹,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12′) and R^(G14′), together with the carbon atoms to which each isattached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G12′), R^(G13′), and R^(G14′) is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G12′), R^(G13′), and R^(G14′) is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G12′) and R^(G14′), together with the carbonatoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G12′), R^(G13′), and R^(G14′) is A¹; or

is substituted with A¹.

In some embodiments, R^(7″) is

In some embodiments, R^(7′) is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(7′)is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(7′) is H,

In some embodiments, R^(7′) is H or

In some embodiments, R^(7′) is H. In some embodiments, R^(7′) is

In some embodiments, G″ is optionally substituted C₃-C₁₀ carbocyclyl oroptionally substituted C₂-C₉ heterocyclyl. In some embodiments, G″ isoptionally substituted C₆-C₁₀ aryl or optionally substituted C₂-C₉heteroaryl.

In some embodiments, G″ is optionally substituted C₃-C₁₀ carbocyclyl. Insome embodiments, G is optionally substituted C₆-C₁₀ aryl. In someembodiments, G is optionally substituted C₂-C₉ heterocyclyl. In someembodiments, G″ is optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G″ is

where

each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4)and R^(G5), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is Cl or F; and R^(G5) is H. In some embodiments, R^(G1) is H;R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2)

is R^(G3) is

R^(G4) is

and R^(G5) is H.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl. In someembodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6) is H,

In some embodiments, R^(G6) is H or

In some embodiments, R^(G6) is H.

In some embodiments, R^(G1) is H, F,

In some embodiments, R^(G1) is H.

In some embodiments, R^(G2) is H, F,

In some embodiments, R^(G2) is H.

In some embodiments, R^(G3) is H, F,

In some embodiments, R^(G3) is H.

In some embodiments, R^(G4) is H, F,

In some embodiments, R^(G4) is H.

In some embodiments, R^(G5) is H, F,

In some embodiments, R^(G5) is H.

In some embodiments, one or more of R^(G1), R^(G2), R^(G3), R^(G4), andR^(G5) is H. In some embodiments, two or more of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is H. In some embodiments, three or more of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is H. In some embodiments, each ofR^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is H.

In some embodiments, G″ is

where

each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is, independently,H, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/or R^(G10)and R^(G11), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/orR^(G10) and R^(G11), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, F, Cl,

In some embodiments, R^(G8) is

In some embodiments, G″ is

In some embodiments, R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.

In some embodiments, G″ is

where

each of R^(G12), R^(G13), and R^(G14) is, independently, H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G12), R^(G13), and R^(G14) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, A has the structure of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIId:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIj:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIk:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIm:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIn:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIo:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIp:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIq:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIr:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIs:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIt:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIu:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIv:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety includes the structure ofFormula Y:

where

A² is a bond between the degradation moiety and the linker;

v1 is 0, 1, 2, 3, 4, or 5;

u1 is 1, 2, or 3;

T¹ is a bond or

T² is

R^(5A) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each R^(J1) is, independently, halogen, optionally substituted C₁-C₆alkyl, or optionally substituted C₁-C₆ heteroalkyl;

J^(A) is absent, O, optionally substituted amino, optionally substitutedC₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl; and

J is absent, optionally substituted C₃-C₁₀ carbocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉heterocyclylene, or optionally substituted C₂-C₉ heteroarylene, or apharmaceutically acceptable salt thereof.

In some embodiments, T² is

In some embodiments, T² is

In some embodiments, T² is

In some embodiments, T² is

In some embodiments, the structure of Formula Y has the structure ofFormula Y1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, T¹ is a bond. In some embodiments, T¹ is

In some embodiments, the structure of Formula Y has the structure ofFormula Y2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Y has the structure ofFormula Z:

or a pharmaceutically acceptable salt thereof.

In some embodiments, u1 is 1. In some embodiments, u1 is 2. In someembodiments u1 is 3.

In some embodiments, the structure of Formula Z has the structure ofFormula AA0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J^(A) is absent. In some embodiments, J^(A) isoptionally substituted C₁-C₆ alkyl. In some embodiments, J^(A) isoptionally substituted C₁-C₆ heteroalkyl. In some embodiments, J^(A) isO or optionally substituted amino.

In some embodiments, J^(A) is

In some embodiments, the structure of Formula AA0 has the structure ofFormula AA0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0.In some embodiments, v1 is 1. In some embodiments, v1 is 2. In someembodiments, v1 is 3.

In some embodiments, the structure of Formula AA has the structure ofFormula AA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AB has the structure ofFormula AB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AC has the structure ofFormula AC1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J is absent. In some embodiments, J is optionallysubstituted C₃-C₁₀ carbocyclylene or optionally substituted C₆-C₁₀arylene. In some embodiments, J is optionally substituted C₂-C₉heterocyclylene or optionally substituted C₂-C₉ heteroarylene.

In some embodiments, J is optionally substituted heterocyclylene. Insome embodiments, J is optionally substituted C₆-C₁₀ arylene.

In some embodiments, J is

In some embodiments, the structure of Formula AA has the structure ofFormula AA2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(A5) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(A5) is H or methyl. In some embodiments, R^(A5)is H. In some embodiments, R^(A5) is methyl. In some embodiments, R^(A5)is

In some embodiments, the structure of Formula AA has the structure ofFormula A:

where

Y1 is

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(A6) is H or optionally substituted C₁-C₆ alkyl; and R^(A7) is H oroptionally substituted C₁-C₆ alkyl; or R^(A6) and R^(A7), together withthe carbon atom to which each is bound, combine to form optionallysubstituted C₃-C₆ carbocyclyl or optionally substituted C₂-C₅heterocyclyl; or R^(A6) and R^(A7), together with the carbon atom towhich each is bound, combine to form optionally substituted C₃-C₆carbocyclyl or optionally substituted C₂-C₅ heterocyclyl;

R^(A8) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A²,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(A1) and R^(A2), R^(A2) and R^(A3), and/orR^(A3) and R^(A4), together with the carbon atoms to which each isattached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, each of R^(A6) and R^(A7) is, independently, H, F,

or R^(A6) and R^(A7), together with the carbon atom to which each isbound, combine to form

In some embodiments, R^(A6) is H and R^(A7) is H.

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, the structure of Formula A has the structure ofFormula A1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A6:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A7:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A8:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A9:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A10:

or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein the structure of Formula A is

or derivative or analog thereof.

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula A is

or derivative or analog thereof.

In some embodiments,

where R^(A9) is H, A², optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl.

In some embodiments, the structure of Formula A is

In some embodiments, R^(A9) is H, A², or optionally substituted C₁-C₆alkyl. In some embodiments, R^(A9) is H, A², or methyl. In someembodiments, R^(9A) is H. In some embodiments, R^(9A) is methyl. In someembodiments, R^(A9) is A².

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula AA has the structure ofFormula B:

where

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A²,halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(A1) and R^(A2), R^(A2) and R^(A3), and/orR^(A3) and R^(A4), together with the carbon atoms to which each isattached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, the structure of Formula B has the structure ofFormula B1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the ubiquitin ligase binding moiety comprises a vonHippel-Lindau ligand.

In some embodiments, the von Hippel-Lindau ligand has the structure of

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula C:

where

R^(B1) is H, A², optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(B2) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(B3) is A², optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;

R^(B4) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

R^(B5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

v2 is 0, 1, 2, 3, or 4;

each R^(B6) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;and

each of R^(B7) and R^(B8) is, independently, H, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₆-C₁₀ aryl,

where one of R^(B1) and R^(B3) is A², or a pharmaceutically acceptablesalt thereof.

In some embodiments, the structure of Formula C is

or derivative or analog thereof.

In some embodiments, the structure of Formula C is

In some embodiments, the degrader moiety includes the structure ofFormula D:

where

A² is a bond between B and the linker;

each of R^(C1), R^(C2), and R^(C7) is, independently, H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;

R^(C3) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

R^(C5) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

v3 is 0, 1, 2, 3, or 4;

each R^(C8) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v4 is 0, 1, 2, 3, or 4; and

each R^(C9) is, independently, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula D is

or derivative or analog thereof.

In some embodiments, the degrader moiety includes the structure ofFormula E:

where

A² is a bond between B and the linker;

each of R^(C10) and R^(C11) is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;

v5 is 0, 1, 2, 3, or 4;

each R^(C12) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v6 is 0, 1, 2, 3, or 4; and

each R²¹ is, independently, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or apharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula E is

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FA:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

is a single bond or a double bond;

u2 is 0, 1, 2, or 3;

A² is a bond between the degrader and the linker;

Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

Y^(Fb) is NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O, or S;

Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of R^(Fb), R^(Fc), R^(Fd), and R^(Fe) is, independently, H, alkyl,aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl,alkoxy, amino, —NHalkyl, or —NaIkyl₂;

or R^(Fb) and R^(Fc), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; and

or R^(Fd) and R^(Fb), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);

Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and Y^(Ff) thatcontains 1 to 5 contiguous carbon atoms that form a 3 to 8-memberedring,

-   -   wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen,        oxygen, or sulfur atom;    -   wherein one of the ring atoms is substituted with A² and the        others are substituted with one or more groups independently        selected from H and R^(FF1); and    -   wherein the contiguous atoms of Y^(Fe) can be attached through a        single or double bond;

each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl, aliphatic,heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy,aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl;

each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic,including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic,including alkyl), —N(aliphatic including alkyl)(aliphatic includingalkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl,—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic,cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or—C(O)Oalkyl,

wherein if Y^(Fd) or Y^(Ff) is substituted with A², then Y^(Fe) is abond, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FA has the structure ofFormula FA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FB:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

A² is a bond between the degrader and the linker;

Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of Y^(Fb) and Y^(Fg) is, independently, NH, NR^(FF1), CH₂,CHR^(FF1), C(R^(FF1))₂, O, or S;

Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of R^(Fb), R^(Fc), R^(Fd), R^(Fe), R^(Ff), and R^(Fg) is,independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl,carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —NaIkyl₂;

or R^(Fb) and R^(Fc), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Ff) and R^(Fg), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fb), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R^(Fd) and R^(Ff), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R^(Fb) and R^(Fg), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);

Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and Y^(Ff) thatcontains 1 to 5 contiguous carbon atoms that forma 3 to 8-membered ring.

-   -   wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen,        oxygen, or sulfur atom;    -   wherein one of the ring atoms is substituted with A² and the        others are substituted with one or more groups independently        selected from H and R^(FF1); and    -   wherein the contiguous atoms of Y^(Fe) can be attached through a        single or double bond;

each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl, aliphatic,heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy,aryl, heteroaryl, heterocyclyl, alkylamino, akylhydroxyl, or haloalkyl;

each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic,including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic,including alkyl), —N(aliphatic including alkyl)(aliphatic includingalkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl,—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic,cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or—C(O)Oalkyl,

wherein if Y^(Fd) or Y^(Ff) is substituted with A², then Y^(Fe) is abond, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FB has the structure ofFormula FB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula F1:

where A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(F1) is absent. In some embodiments, R^(F1) is O.

In some embodiments, the structure of Formula F1 is

In some embodiments, the degradation moiety includes the structureFormula F2:

where A² is a bond between the degrader and the linker; and Y² is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y² is NH. In some embodiments, Y² is CH₂.

In some embodiments, structure of Formula F2 is

In some embodiments, the degradation moiety includes the structureFormula G:

where A² is a bond between the degrader and the linker; and Y³ is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y³ is NH. In some embodiments, Y³ is CH₂.

In some embodiments, structure of Formula G is

The degradation moiety may also include structures found in, e.g.,WO2017/197036; WO2019/204354, WO2019/236483, WO2020/010177; andWO2020/010227, the structures of which are herein incorporated byreference.

In some embodiments, the linker has the structure of Formula IV:

A¹-(B¹)_(f)—(C¹)_(g)—(B²)_(h)-(D)-(B³)_(i)—(C²)_(j)—(B⁴)_(k)-A²  FormulaIV

where

A¹ is a bond between the linker and A;

A² is a bond between B and the linker;

each of B¹, B², B³, and B⁴ is, independently, optionally substitutedC₁-C₂ alkylene, optionally substituted C₁-C₃ heteroalkylene, O, S,S(O)₂, or NR^(N);

each R^(N) is, independently, H, optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, or optionally substituted C₁₋₇ heteroalkyl;

each of C¹ and C² is, independently, carbonyl, thiocarbonyl, sulphonyl,or phosphoryl;

each of f, g, h, i, j, and k is, independently, 0 or 1; and

D is optionally substituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀alkenylene, optionally substituted C₂₋₁₀ alkynylene, optionallysubstituted C₂₋₆ heterocyclylene, optionally substituted C₆₋₁₂ arylene,optionally substituted C₂-C₁₀ polyethylene glycol, or optionallysubstituted C₁₋₁₀ heteroalkylene, or a chemical bond linkingA¹-(B¹)_(f)—(C¹)_(g)—(B²)_(h)— to —(B³)_(i)—(C²)_(j)—(B⁴)_(k)-A².

In some embodiments, each of B¹, B², B³, and B⁴ is, independently,optionally substituted C₁-C₄ alkylene, optionally substituted C₁-C₄heteroalkylene, or NR^(N).

In some embodiments, each R^(N) is, independently, H or optionallysubstituted C₁-C₄ alkylene.

In some embodiments, each R^(N) is, independently, H or methyl.

In some embodiments, each of B¹ and B⁴ is, independently,

In some embodiments, B¹ is

In some embodiments, each of C¹ and C² is, independently,

In some embodiments, C¹ is

In some embodiments, B² is NR^(N). In some embodiments, B² is optionallysubstituted C₁-C₄ alkylene.

In some embodiments, f is 0. In some embodiments, f is 1. In someembodiments, g is 1. In some embodiments, h is 0. In some embodiments, his 1. In some embodiments, i is 0. In some embodiments, j is 0. In someembodiments, k is 0.

In some embodiments, the linker has the structure of

wherein

x is 1, 2, 3, 4, 5, 6, 7, or 8;

y is 1, 2, 3, or 4;

R^(x) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(y) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

W is O or NR^(w), wherein R^(w) is H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl.

In some embodiments, the linker has the structure of

In some embodiments, R^(x) is H or me optionally substituted C₁-C₆alkyl. In some embodiments, R^(y) is H or optionally substituted C₁-C₆alkyl. In some embodiments, R^(w) is H or optionally substituted C₁-C₆alkyl.

In some embodiments, R^(x) is H or methyl. In some embodiments, R^(y) isH or methyl. In some embodiments, R^(w) is H or methyl.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of Formula V:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)—(F³)_(o2)-(E²)_(p)-A²,  FormulaV

where

A¹ is a bond between the linker and A;

A² is a bond between B and the linker;

each of m, n, o1, o2, and p is, independently, 0 or 1;

each of E¹ and E² is, independently, O, S, NR^(N), optionallysubstituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀ alkenylene,optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₁₀polyethylene glycol, or optionally substituted C₁₋₁₀ heteroalkylene;

E³ is optionally substituted C₁-C₆ alkylene, optionally substitutedC₁-C₆ heteroalkylene, O, S, or NR^(N);

each R^(N) is, independently, H, optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, or optionally substituted C₁₋₇ heteroalkyl;

C³ is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and

each of F¹, F², and F³ is, independently, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂₋₁₀ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, or optionally substituted C₂-C₉heteroarylene.

In some embodiments, the linker has the structure of Formula Va:

A¹-(E¹)-(F¹)—(C³)_(m)-(E²)_(p)-A².  Formula Va

In some embodiments, the linker has the structure of Formula Vb:

A¹-(E¹)-(F¹)-(E²)_(p)-A².  Formula Vb

In some embodiments, the linker has the structure of Formula Vc:

A¹-(E¹)-(F¹)-A².  Formula Vc

In some embodiments, the linker has the structure of Formula Vd:

A¹-(E¹)-(F¹)—(C³)_(m)—(F²)_(o1)-A².  Formula Vd

In some embodiments, the linker has the structure of Formula Ve:

A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².  Formula Ve

In some embodiments, the linker has the structure of Formula Vf:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².  Formula Vf

In some embodiments, the linker has the structure of Formula Vg:

A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A²,  Formula Vg

In some embodiments, each of E¹ and E² is, independently, NR^(N),optionally substituted C₁₋₁₀ alkylene, optionally substituted C₂-C₁₀polyethylene glycolene, or optionally substituted C₁₋₁₀ heteroalkylene.

In some embodiments, E³ is optionally substituted C₁-C₆ alkylene, O, S,or NR^(N); In some embodiments, E³ is optionally substituted C₁-C₆alkylene. In some embodiments, E³ is optionally substituted C₁-C₃alkylene. In some embodiments, E³ is O, S, or NR^(N).

In some embodiments, E³ is C₁-C₆ alkylene. In some embodiments, E³ isC₁-C₃ alkylene. In some embodiments, E³ is O.

In some embodiments, E³ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E³ is

In some embodiments, each R^(N) is, independently, H or optionallysubstituted C₁₋₄ alkyl.

In some embodiments, each R^(N) is, independently, H or methyl.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

where

b is 0, 1, 2, 3, 4, 5, or 6;

R^(a) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

R^(c) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, R^(a) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(b) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(c) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(a) is H or methyl. In some embodiments, R^(b) isH or methyl. In some embodiments, R^(c) is H or methyl.

In some embodiments, b is 0, 1, 2, or 3. In some embodiments, b is 0. Insome embodiments, b is 1. In some embodiments, b is 2. In someembodiments, b is 3.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E² is O, NR^(w),

wherein

c is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

d is 0, 1, 2, or 3;

e is 0, 1, 2, 3, 4, 5, or 6;

f is 0, 1, 2, 3, or 4;

R^(d) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(e) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(f) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(g) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

W is O or NR^(w), wherein R^(w) is H or optionally substituted C₁-C₆alkyl.

In some embodiments, E² is O, NR^(w),

In some embodiments, R^(d) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(e) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(f) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(g) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(w) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(d) is H or methyl. In some embodiments, R^(e) isH or methyl. In some embodiments, R^(f) is H or methyl. In someembodiments, R^(g) is H or methyl. In some embodiments, R^(w) is H ormethyl.

In some embodiments, E² is

In some embodiments, E² is O,

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₃-C₁₀ carbocyclylene.

In some embodiments, the C₃-C₁₀ carbocyclylene is monocyclic. In someembodiments, the C₃-C₁₀ carbocyclylene is polycyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bicyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bridged. In someembodiments, the C₃-C₁₀ carbocyclylene is fused. In some embodiments,the C₃-C₁₀ carbocyclylene is spirocyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is

In some embodiments, F² is

In some embodiments, the C₃-C₁₀ carbocyclylene is

In some embodiments, F¹ is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the C₂-C₉ heterocyclylene includes a quaternaryamine.

In some embodiments, the C₂-C₉ heterocyclylene is

where

q1 is 0, 1, 2, 3, or 4;

q2 is 0, 1, 2, 3, 4, 5, or 6;

q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

each R^(h) is, independently, ²H, halogen, optionally substituted C₁-C₆alkyl, OR^(i2), or NR^(i3)R^(i4); or two R^(h) groups, together with thecarbon atom to which each is attached, combine to form optionallysubstituted C₃-C₁₀ carbocyclyl or optionally substituted C₂-C₉heterocyclyl; or two R^(h) groups, together with the carbon atoms towhich each is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl;

R^(i1) is H or optionally substituted C₁-C₆ alkyl;

R^(i2) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(i3) is H or optionally substituted C₁-C₆ alkyl; and

R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,R^(i1) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i2) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i3) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,each R^(h) is, independently, halogen, optionally substituted C₁-C₆alkyl, or NR^(i3)R^(i4).

In some embodiments, each R^(h) is, independently, ²H, halogen, cyano,optionally substituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In someembodiments, two R^(h) groups, together with the carbon atom to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl. In someembodiments, two R^(h) groups, together with the carbon atoms to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each R^(h) is, independently, ²H, F, methyl,

In some embodiments, each R^(h) is, independently, F, methyl, orNR^(i3)R^(i4).

In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is O. Insome embodiments, q1 is 1. In some embodiments, q1 is 2.

In some embodiments, q2 is 0, 1, or 2. In some embodiments, q2 is 0. Insome embodiments, q2 is 1. In some embodiments, q2 is 2.

In some embodiments, q3 is 0, 1, or 2. In some embodiments, q3 is 0. Insome embodiments, q3 is 1. In some embodiments, q3 is 2.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F³ is

In some embodiments, F³ is

In some embodiments, R^(i1) is H or methyl. In some embodiments, R^(i2)is H or methyl. In some embodiments, R^(i3) is H or methyl. In someembodiments, R^(i4) is H or methyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F³ is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₆-C₁₀ arylene.

In some embodiments, the C₆-C₁₀ arylene is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heteroarylene.

In some embodiments, the C₂-C₉ heteroarylene is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, C³ is

In some embodiments, C³ is

In some embodiments, m is 1. In some embodiments, p is 1.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of:

In some embodiments, the linker is absent.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂₋₁₀ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, or optionally substituted C₂-C₉heteroarylene.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene or optionally substituted C₂₋₁₀ heterocyclylene. In someembodiments, the linker is optionally substituted C₆-C₁₀ arylene oroptionally substituted C₂-C₉ heteroarylene.

In some embodiments, the linker is optionally substituted C₂₋₁₀heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the compound has the structure of any one ofcompounds D1-D31 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure ofcompounds D32-D184 in Table 2B, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D185-D316 in Table 2C, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the compound has the structure of any one ofcompounds D1, D7, D15-D21, D23, and D27-D30 in Table 2A, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound has the structure of any one of compounds D32-D42, D46,D48-D63, D65-D73, D75-D83, D85-D87, D89-D93, D95-D116, D118, D120-D164,D166-D168, D170, D171, D173, D174, D176-D178, D180, D182, and D184 inTable 2B, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound has the structure of any one of compoundsD185-D190, D192-D204, D248, D254-D258, D260, D262-D269, D271-D280, D284,D286-D291, and D293-D316 in Table 2C, or a pharmaceutically acceptablesalt thereof.

In an aspect, the disclosure features compounds D1-D31 in Table 2A, or apharmaceutically acceptable salt thereof.

In an aspect, the disclosure features compounds D32-D184 in Table 2B, ora pharmaceutically acceptable salt thereof.

In an aspect, the disclosure features compounds D185-D316 in Table 2C,or a pharmaceutically acceptable salt thereof.

TABLE 2A Compounds D1-D31 of the Disclosure Com- pound No. Structure D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

D26

D27

D28

D29

D30

D31

TABLE 2B Compounds D32-D184 of the Disclosure Com- pound No. StructureD32

D33

D34

D35

D36

D37

D38

D39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

D57

D58

D59

D60

D61

D62

D63

D64

D65

D66

D67

D68

D69

D70

D71

D72

D73

D74

D75

D76

D77

D78

D79

D80

D81

D82

D83

D84

D85

D86

D87

D88

D89

D90

D91

D92

D93

D94

D95

D96

D97

D98

D99

D100

D101

D102

D103

D104

D105

D106

D107

D108

D109

D110

D111

D112

D113

D114

D115

D116

D117

D118

D119

D120

D121

D122

D123

D124

D125

D126

D127

D128

D129

D130

D131

D132

D133

D134

D135

D136

D137

D138

D139

D140

D141

D142

D143

D144

D145

D146

D147

D148

D149

D150

D151

D152

D153

D154

D155

D156

D157

D158

D159

D160

D161

D162

D163

D164

D165

D166

D167

D168

D169

D170

D171

D172

D173

D174

D175

D176

D177

D178

D179

D180

D181

D182

D183

D184

TABLE 2C Compounds D185-D316 of the Disclosure Compound No. StructureD185

D186

D187

D188

D189

D190

D191

D192

D193

D194

D195

D196

D197

D198

D199

D200

D201

D202

D203

D204

D205

D206

D207

D208

D209

D210

D211

D212

D213

D214

D215

D216

D217

D218

D219

D220

D221

D222

D223

D224

D225

D226

D227

D228

D229

D230

D231

D232

D233

D234

D235

D236

D237

D238

D239

D240

D241

D242

D243

D244

D245

D246

D247

D248

D249

D250

D251

D252

D253

D254

D255

D256

D257

D258

D259

D260

D261

D262

D263

D264

D265

D266

D267

D268

D269

D270

D271

D272

D273

D274

D275

D276

D277

D278

D279

D280

D281

D282

D283

D284

D285

D286

D287

D288

D289

D290

D291

D292

D293

D294

D295

D296

D297

D298

D299

D300

D301

D302

D303

D304

D305

D306

D307

D308

D309

D310

D311

D312

D313

D314

D315

D316

In another aspect, the disclosure features a pharmaceutical compositionincluding any of the foregoing compounds, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable excipient.

In an aspect, the disclosure features a method of inhibiting the leveland/or activity of BRD9 in a cell, the method involving contacting thecell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In another aspect, the disclosure features a method of reducing thelevel and/or activity of BRD9 in a cell, the method involving contactingthe cell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In an aspect, the disclosure features a method of treating a BAFcomplex-related disorder in a subject in need thereof, the methodinvolving administering to the subject an effective amount of any of theforegoing compounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, the BAFcomplex-related disorder is cancer. In some embodiments, the BAFcomplex-related disorder is infection.

In another aspect, the disclosure features a method of treating anSS18-SSX fusion protein-related disorder in a subject in need thereof,the method involving administering to the subject an effective amount ofany of the foregoing compounds, or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof. In some embodiments,the SS18-SSX fusion protein-related disorder is cancer. In someembodiments, the SS18-SSX fusion protein-related disorder is infection.In some embodiments of any of the foregoing methods, the SS18-SSX fusionprotein is a SS18-SSX1 fusion protein, a SS18-SSX2 fusion protein, or aSS18-SSX4 fusion protein.

In yet another aspect, the disclosure features a method of treating aBRD9-related disorder in a subject in need thereof, the method involvingadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, theBRD9-related disorder is cancer. In some embodiments, the BRD9-relateddisorder is infection.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)-+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In some embodiments, the infection is viral infection (e.g., aninfection with a virus of the Retroviridae family such as thelentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)); Flaviviridae family (e.g. hepatitis C virus (HCV));Adenoviridae family (e.g. Human Adenovirus); Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus); Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)); Parvoviridae family (e.g.Parvovirus B19); Polyomaviridae family (e.g. JC virus and BK virus);Paramyxoviridae family (e.g. Measles virus); or Togaviridae family (e.g.Rubella virus)). In some embodiments, the disorder is Coffin Siris,Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or MultipleMeningioma. In an aspect, the disclosure features a method of treating acancer in a subject in need thereof, the method including administeringto the subject an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or any of the foregoingpharmaceutical compositions.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)-+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In another aspect, the disclosure features a method for treating a viralinfection in a subject in need thereof. This method includesadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or any of theforegoing pharmaceutical compositions. In some embodiments, the viralinfection is an infection with a virus of the Retroviridae family suchas the lentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)), Flaviviridae family (e.g. hepatitis C virus (HCV)),Adenoviridae family (e.g. Human Adenovirus), Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus), Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g.Parvovirus B19), Polyomaviridae family (e.g. JC virus and BK virus),Paramyxoviridae family (e.g. Measles virus), Togaviridae family (e.g.Rubella virus).

In another embodiment of any of the foregoing methods, the methodfurther includes administering to the subject an additional anticancertherapy (e.g., chemotherapeutic or cytotoxic agent or radiotherapy).

In particular embodiments, the additional anticancer therapy is: achemotherapeutic or cytotoxic agent (e.g., doxorubicin or ifosfamide), adifferentiation-inducing agent (e.g., retinoic acid, vitamin D,cytokines), a hormonal agent, an immunological agent, or ananti-angiogenic agent. Chemotherapeutic and cytotoxic agents include,but are not limited to, alkylating agents, cytotoxic antibiotics,antimetabolites, vinca alkaloids, etoposides, and others (e.g.,paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list ofadditional compounds having anticancer activity can be found in L.Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman's ThePharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGrawHill Companies, New York, N.Y.

In particular embodiments, the compound of the invention and theadditional anticancer therapy and any of the foregoing compounds orpharmaceutical compositions are administered within 28 days of eachother (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in anamount that together are effective to treat the subject.

Chemical Terms

The terminology employed herein is for the purpose of describingparticular embodiments and is not intended to be limiting.

For any of the following chemical definitions, a number following anatomic symbol indicates that total number of atoms of that element thatare present in a particular chemical moiety. As will be understood,other atoms, such as hydrogen atoms, or substituent groups, as describedherein, may be present, as necessary, to satisfy the valences of theatoms. For example, an unsubstituted C₂ alkyl group has the formula—CH₂CH₃. When used with the groups defined herein, a reference to thenumber of carbon atoms includes the divalent carbon in acetal and ketalgroups but does not include the carbonyl carbon in acyl, ester,carbonate, or carbamate groups. A reference to the number of oxygen,nitrogen, or sulfur atoms in a heteroaryl group only includes thoseatoms that form a part of a heterocyclic ring.

Herein a phrase of the form “optionally substituted X” (e.g., optionallysubstituted alkyl) is intended to be equivalent to “X, wherein X isoptionally substituted” (e.g., “alkyl, wherein said alkyl is optionallysubstituted”). It is not intended to mean that the feature “X” (e.g.,alkyl) per se is optional. As described herein, certain compounds ofinterest may contain one or more “optionally substituted” moieties. Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that one or more hydrogens of the designatedmoiety are replaced with a suitable substituent, e.g., any of thesubstituents or groups described herein. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby the present disclosure are preferably those that result in theformation of stable or chemically feasible compounds. The term “stable”,as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and, in certain embodiments, their recovery, purification, and use forone or more of the purposes disclosed herein.

The term “aliphatic,” as used herein, refers to a saturated orunsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” isintended herein to include, but is not limited to, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thusincorporates each of these definitions. In one embodiment, “aliphatic”is used to indicate those aliphatic groups having 1-20 carbon atoms. Thealiphatic chain can be, for example, mono-unsaturated, di-unsaturated,tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphaticgroups can be in a cis or trans configuration. In one embodiment, thealiphatic group contains from 1 to about 12 carbon atoms, more generallyfrom 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In oneembodiment, the aliphatic group contains from 1 to about 8 carbon atoms.In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, or C₁-C₆. The specified ranges as used herein indicate analiphatic group having each member of the range described as anindependent species. For example, the term C₁-C₆ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to meanthat each of these is described as an independent species. For example,the term C₁-C₄ aliphatic as used herein indicates a straight or branchedalkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atomsand is intended to mean that each of these is described as anindependent species. In one embodiment, the aliphatic group issubstituted with one or more functional groups that results in theformation of a stable moiety.

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety that contains at least one heteroatom in the chain, for example,an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate,nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.In one embodiment, the only heteroatom is nitrogen. In one embodiment,the only heteroatom is oxygen. In one embodiment, the only heteroatom issulfur. “Heteroaliphatic” is intended herein to include, but is notlimited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, and alkyl-O-haloalkyl.

The term “acyl,” as used herein, represents a hydrogen or an alkyl groupthat is attached to a parent molecular group through a carbonyl group,as defined herein, and is exemplified by formyl (i.e., a carboxyaldehydegroup), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplaryunsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1to 21 carbons.

The term “alkyl,” as used herein, refers to a branched or straight-chainmonovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbonatoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbonatoms, or 1 to 3 carbon atoms). An “alkylene” is a divalent alkyl group.

The term “alkenyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon double bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkenylene” is a divalent alkenyl group.

The term “alkynyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon triple bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkynylene” is a divalent alkynyl group.

The term “amino,” as used herein, represents —N(R^(N1))₂, wherein eachR^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂R^(N2),SOR^(N2), an N-protecting group, alkyl, alkoxy, aryl, arylalkyl,cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others describedherein), wherein each of these recited R^(N1) groups can be optionallysubstituted; or two R^(N1) combine to form an alkylene orheteroalkylene, and wherein each R^(N2) is, independently, H, alkyl, oraryl. The amino groups of the compounds described herein can be anunsubstituted amino (i.e., —NH₂) or a substituted amino (i.e.,—N(R^(N1))₂).

The term “aryl,” as used herein, refers to an aromatic mono- orpolycarbocyclic radical of, e.g., 6 to 12, carbon atoms having at leastone aromatic ring. Examples of such groups include, but are not limitedto, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl,indanyl, and 1H-indenyl.

The term “arylalkyl,” as used herein, represents an alkyl groupsubstituted with an aryl group. Exemplary unsubstituted arylalkyl groupsare from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons,such as C₁-C₆ alkyl C₆-C₁₀ aryl, C₁-C₁₀ alkyl C₆-C₁₀ aryl, or C₁-C₂₀alkyl C₆-C₁₀ aryl), such as, benzyl and phenethyl. In some embodiments,the alkyl and the aryl each can be further substituted with 1, 2, 3, or4 substituent groups as defined herein for the respective groups.

The term “azido,” as used herein, represents a —N₃ group.

The term “bridged cyclyl,” as used herein, refers to a bridgedpolycyclic group of 5 to 20 atoms, containing from 1 to 3 bridges.Bridged cyclyl includes bridged carbocyclyl (e.g., norbornyl) andbridged heterocyclyl (e.g., 1,4-diazabicyclo[2.2.2]octane).

The term “cyano,” as used herein, represents a —CN group.

The term “carbocyclyl,” as used herein, refers to a non-aromatic C₃-C₁₂,monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure inwhich the rings are formed by carbon atoms. Carbocyclyl structuresinclude cycloalkyl groups (e.g., cyclohexyl) and unsaturated carbocyclylradicals (e.g., cyclohexenyl). Polycyclic carbocyclyl includesspirocyclic carbocyclyl, bridged carbocyclyl, and fused carbocyclyl. A“carbocyclylene” is a divalent carbocyclyl group.

The term “cycloalkyl,” as used herein, refers to a saturated,non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10,preferably 3 to 6 carbon atoms. This term is further exemplified byradicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and adamantyl.

The terms “halo” or “halogen,” as used herein, mean a fluorine (fluoro),chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkyl groups. Examples ofheteroalkyl groups are an “alkoxy” which, as used herein, refers toalkyl-O— (e.g., methoxy and ethoxy), and an “alkylamino” which, as usedherein, refers to —N(alkyl)R^(Na), where R^(Na) is H or alkyl (e.g.,methylamino). A “heteroalkylene” is a divalent heteroalkyl group.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkenyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkenyl groups. Examples ofheteroalkenyl groups are an “alkenoxy” which, as used herein, refers toalkenyl-O—. A “heteroalkenylene” is a divalent heteroalkenyl group.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkynyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkynyl groups. Examples ofheteroalkynyl groups are an “alkynoxy” which, as used herein, refers toalkynyl-O—. A “heteroalkynylene” is a divalent heteroalkynyl group.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor polycyclic structure of 5 to 12 atoms having at least one aromaticring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen,and sulfur, with the remaining ring atoms being carbon. One or two ringcarbon atoms of the heteroaryl group may be replaced with a carbonylgroup. Examples of heteroaryl groups are pyridyl, pyrazoyl,benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl,and thiazolyl. A “heteroarylene” is a divalent heteroaryl group.

The term “heteroarylalkyl,” as used herein, represents an alkyl groupsubstituted with a heteroaryl group. Exemplary unsubstitutedheteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heteroaryl, C₁-C₁₀ alkylC₂-C₉ heteroaryl, or C₁-C₂₀ alkyl C₂-C₉ heteroaryl). In someembodiments, the alkyl and the heteroaryl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “heterocyclyl,” as used herein, refers a monocyclic orpolycyclic radical (e.g., bicyclic or tricyclic) having 3 to 12 atomshaving at least one non-aromatic ring containing 1, 2, 3, or 4 ringatoms selected from N, O, or S, and no aromatic ring containing any N,O, or S atoms. Polycyclic heterocyclyl includes spirocyclicheterocyclyl, bridged heterocyclyl, and fused heterocyclyl. Examples ofheterocyclyl groups include, but are not limited to, morpholinyl,thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A“heterocyclylene” is a divalent heterocyclyl group.

The term “heterocyclylalkyl,” as used herein, represents an alkyl groupsubstituted with a heterocyclyl group. Exemplary unsubstitutedheterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heterocyclyl, C₁-C₁₀alkyl C₂-C₉ heterocyclyl, or C₁-C₂₀ alkyl C₂-C₉ heterocyclyl). In someembodiments, the alkyl and the heterocyclyl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “hydroxyalkyl,” as used herein, represents alkyl groupsubstituted with an —OH group.

The term “hydroxyl,” as used herein, represents an —OH group.

The term “imine,” as used herein, represents ═NR^(N) group, where R^(N)is, e.g., H or alkyl.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, “Protective Groups in Organic Synthesis,” 3rd Edition (JohnWiley & Sons, New York, 1999). N-protecting groups include, but are notlimited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotectedD, L, or D, L-amino acids such as alanine, leucine, and phenylalanine;sulfonyl-containing groups such as benzenesulfonyl, andp-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl,arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl,and silyl groups, such as trimethylsilyl. Preferred N-protecting groupsare alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl(Cbz).

The term “nitro,” as used herein, represents an —NO₂ group.

The term “oxo,” as used herein, represents an ═O group.

The term “thiol,” as used herein, represents an —SH group.

The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclylgroups may be substituted or unsubstituted. When substituted, there willgenerally be 1 to 4 substituents present, unless otherwise specified.Substituents include, for example: alkyl (e.g., unsubstituted andsubstituted, where the substituents include any group described herein,e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstitutedphenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl),halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted andunsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl,amino (e.g., NH₂ or mono- or dialkyl amino), azido, cyano, nitro, oxo,sulfonyl, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl,and heterocyclyl groups may also be substituted with alkyl(unsubstituted and substituted such as arylalkyl (e.g., substituted andunsubstituted benzyl)).

Compounds described herein (e.g., compounds of the invention) can haveone or more asymmetric carbon atoms and can exist in the form ofoptically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, or mixtures ofdiastereoisomeric racemates. The optically active forms can be obtainedfor example by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbent oreluant). That is, certain of the disclosed compounds may exist invarious stereoisomeric forms. Stereoisomers are compounds that differonly in their spatial arrangement. Enantiomers are pairs ofstereoisomers whose mirror images are not superimposable, most commonlybecause they contain an asymmetrically substituted carbon atom that actsas a chiral center. “Enantiomer” means one of a pair of molecules thatare mirror images of each other and are not superimposable.Diastereomers are stereoisomers that are not related as mirror images,most commonly because they contain two or more asymmetricallysubstituted carbon atoms and represent the configuration of substituentsaround one or more chiral carbon atoms. Enantiomers of a compound can beprepared, for example, by separating an enantiomer from a racemate usingone or more well-known techniques and methods, such as, for example,chiral chromatography and separation methods based thereon. Theappropriate technique and/or method for separating an enantiomer of acompound described herein from a racemic mixture can be readilydetermined by those of skill in the art. “Racemate” or “racemic mixture”means a compound containing two enantiomers, wherein such mixturesexhibit no optical activity; i.e., they do not rotate the plane ofpolarized light. “Geometric isomer” means isomers that differ in theorientation of substituent atoms in relationship to a carbon-carbondouble bond, to a cycloalkyl ring, or to a bridged bicyclic system.Atoms (other than H) on each side of a carbon-carbon double bond may bein an E (substituents are on opposite sides of the carbon-carbon doublebond) or Z (substituents are oriented on the same side) configuration.“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule. Certain of the disclosedcompounds may exist in atropisomeric forms. Atropisomers arestereoisomers resulting from hindered rotation about single bonds wherethe steric strain barrier to rotation is high enough to allow for theisolation of the conformers. The compounds described herein (e.g., thecompounds of the invention) may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods. When the stereochemistry of a disclosedcompound is named or depicted by structure, the named or depictedstereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weightrelative to the other stereoisomers. When a single enantiomer is namedor depicted by structure, the depicted or named enantiomer is at least60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When asingle diastereomer is named or depicted by structure, the depicted ornamed diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% byweight pure. Percent optical purity is the ratio of the weight of theenantiomer or over the weight of the enantiomer plus the weight of itsoptical isomer. Diastereomeric purity by weight is the ratio of theweight of one diastereomer or over the weight of all the diastereomers.When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer isnamed or depicted by structure, the depicted or named diastereomer is atleast 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percentpurity by mole fraction is the ratio of the moles of the enantiomer orover the moles of the enantiomer plus the moles of its optical isomer.Similarly, percent purity by moles fraction is the ratio of the moles ofthe diastereomer or over the moles of the diastereomer plus the moles ofits isomer. When a disclosed compound is named or depicted by structurewithout indicating the stereochemistry, and the compound has at leastone chiral center, it is to be understood that the name or structureencompasses either enantiomer of the compound free from thecorresponding optical isomer, a racemic mixture of the compound, ormixtures enriched in one enantiomer relative to its correspondingoptical isomer. When a disclosed compound is named or depicted bystructure without indicating the stereochemistry and has two or morechiral centers, it is to be understood that the name or structureencompasses a diastereomer free of other diastereomers, a number ofdiastereomers free from other diastereomeric pairs, mixtures ofdiastereomers, mixtures of diastereomeric pairs, mixtures ofdiastereomers in which one diastereomer is enriched relative to theother diastereomer(s), or mixtures of diastereomers in which one or morediastereomer is enriched relative to the other diastereomers. Theinvention embraces all of these forms.

Compounds of the present disclosure also include all of the isotopes ofthe atoms occurring in the intermediate or final compounds. “Isotopes”refers to atoms having the same atomic number but different mass numbersresulting from a different number of neutrons in the nuclei. Forexample, isotopes of hydrogen include tritium and deuterium.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Isotopically-labeled compounds(e.g., those labeled with ³H and ¹⁴C)) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C)) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, one or more hydrogenatoms are replaced by ²H or ³H, or one or more carbon atoms are replacedby ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Preparations ofisotopically labelled compounds are known to those of skill in the art.For example, isotopically labeled compounds can generally be prepared byfollowing procedures analogous to those disclosed for compounds of thepresent invention described herein, by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As is known in the art, many chemical entities can adopt a variety ofdifferent solid forms such as, for example, amorphous forms orcrystalline forms (e.g., polymorphs, hydrates, solvate). In someembodiments, compounds of the present invention may be utilized in anysuch form, including in any solid form. In some embodiments, compoundsdescribed or depicted herein may be provided or utilized in hydrate orsolvate form.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present disclosure; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Definitions

In this application, unless otherwise clear from context, (i) the term“a” may be understood to mean “at least one”; (ii) the term “or” may beunderstood to mean “and/or”; and (iii) the terms “including” and“including” may be understood to encompass itemized components or stepswhether presented by themselves or together with one or more additionalcomponents or steps.

As used herein, the terms “about” and “approximately” refer to a valuethat is within 10% above or below the value being described. Forexample, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) may be by any appropriate route.For example, in some embodiments, administration may be bronchial(including by bronchial instillation), buccal, enteral, interdermal,intra-arterial, intradermal, intragastric, intramedullary,intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral,intravenous, intraventricular, mucosal, nasal, oral, rectal,subcutaneous, sublingual, topical, tracheal (including by intratrachealinstillation), transdermal, vaginal, and vitreal.

As used herein, the term “adult soft tissue sarcoma” refers to a sarcomathat develops in the soft tissues of the body, typically in adolescentand adult subjects (e.g., subjects who are at least 10 years old, 11years old, 12 years old, 13 years old, 14 years old, 15 years old, 16years old, 17 years old, 18 years old, or 19 years old). Non-limitingexamples of adult soft tissue sarcoma include, but are not limited to,synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma,dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangiosarcoma,Kaposi's sarcoma, lymphangiosarcoma, malignant peripheral nerve sheathtumor/neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, extraskeletal myxoid chondrosarcoma, and extraskeletalmesenchymal.

The term “antisense,” as used herein, refers to a nucleic acidcomprising a polynucleotide that is sufficiently complementary to all ora portion of a gene, primary transcript, or processed mRNA, so as tointerfere with expression of the endogenous gene (e.g., BRD9).“Complementary” polynucleotides are those that are capable of basepairing according to the standard Watson-Crick complementarity rules.Specifically, purines will base pair with pyrimidines to form acombination of guanine paired with cytosine (G:C) and adenine pairedwith either thymine (A:T) in the case of DNA, or adenine paired withuracil (A:U) in the case of RNA. It is understood that twopolynucleotides may hybridize to each other even if they are notcompletely complementary to each other, provided that each has at leastone region that is substantially complementary to the other.

The term “antisense nucleic acid” includes single-stranded RNA as wellas double-stranded DNA expression cassettes that can be transcribed toproduce an antisense RNA. “Active” antisense nucleic acids are antisenseRNA molecules that are capable of selectively hybridizing with a primarytranscript or mRNA encoding a polypeptide having at least 80% sequenceidentity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) with the targetedpolypeptide sequence (e.g., a BRD9 polypeptide sequence). The antisensenucleic acid can be complementary to an entire coding strand, or to onlya portion thereof. In some embodiments, an antisense nucleic acidmolecule is antisense to a “coding region” of the coding strand of anucleotide sequence. The term “coding region” refers to the region ofthe nucleotide sequence comprising codons that are translated into aminoacid residues. In some embodiments, the antisense nucleic acid moleculeis antisense to a “noncoding region” of the coding strand of anucleotide sequence. The term “noncoding region” refers to 5′ and 3′sequences that flank the coding region that are not translated intoamino acids (i.e., also referred to as 5′ and 3′ untranslated regions).The antisense nucleic acid molecule can be complementary to the entirecoding region of mRNA, or can be antisense to only a portion of thecoding or noncoding region of an mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site. An antisense oligonucleotide can be, forexample, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides inlength.

As used herein, the term “BAF complex” refers to the BRG1- orHRBM-associated factors complex in a human cell.

As used herein, the term “BAF complex-related disorder” refers to adisorder that is caused or affected by the level and/or activity of aBAF complex.

As used herein, the terms “GBAF complex” and “GBAF” refer to a SWI/SNFATPase chromatin remodeling complex in a human cell. GBAF complexsubunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B,BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2,SMARCD3, and SS18. The term “cancer” refers to a condition caused by theproliferation of malignant neoplastic cells, such as tumors, neoplasms,carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, the term “BRD9” refers to bromodomain-containing protein9, a component of the BAF (BRG1- or BRM-associated factors) complex, aSWI/SNF ATPase chromatin remodeling complex, and belongs to family IV ofthe bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene,the nucleic acid sequence of which is set forth in SEQ ID NO: 1. Theterm “BRD9” also refers to natural variants of the wild-type BRD9protein, such as proteins having at least 85% identity (e.g., 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%identity, or more) to the amino acid sequence of wild-type BRD9, whichis set forth in SEQ ID NO: 2.

As used herein, the term “BRD9-related disorder” refers to a disorderthat is caused or affected by the level and/or activity of BRD9. Theterm “cancer” refers to a condition caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, and lymphomas.

As used herein, a “combination therapy” or “administered in combination”means that two (or more) different agents or treatments are administeredto a subject as part of a defined treatment regimen for a particulardisease or condition. The treatment regimen defines the doses andperiodicity of administration of each agent such that the effects of theseparate agents on the subject overlap. In some embodiments, thedelivery of the two or more agents is simultaneous or concurrent and theagents may be co-formulated. In some embodiments, the two or more agentsare not co-formulated and are administered in a sequential manner aspart of a prescribed regimen. In some embodiments, administration of twoor more agents or treatments in combination is such that the reductionin a symptom, or other parameter related to the disorder is greater thanwhat would be observed with one agent or treatment delivered alone or inthe absence of the other. The effect of the two treatments can bepartially additive, wholly additive, or greater than additive (e.g.,synergistic). Sequential or substantially simultaneous administration ofeach therapeutic agent can be effected by any appropriate routeincluding, but not limited to, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents can be administered by the same route orby different routes. For example, a first therapeutic agent of thecombination may be administered by intravenous injection while a secondtherapeutic agent of the combination may be administered orally.

A “compound of the present invention” and similar terms as used herein,whether explicitly noted or not, refers to compounds useful for treatingBAF-related disorders (e.g., cancer or infection) described herein,including, e.g., compounds of Formula I or Formula II (e.g., compoundsof Table 2A, Table 2B, and Table 2C), as well as salts (e.g.,pharmaceutically acceptable salts), solvates, hydrates, stereoisomers(including atropisomers), and tautomers thereof. Those skilled in theart will appreciate that certain compounds described herein can exist inone or more different isomeric (e.g., stereoisomers, geometric isomers,atropisomers, and tautomers) or isotopic (e.g., in which one or moreatoms has been substituted with a different isotope of the atom, such ashydrogen substituted for deuterium) forms. Unless otherwise indicated orclear from context, a depicted structure can be understood to representany such isomeric or isotopic form, individually or in combination.Compounds described herein can be asymmetric (e.g., having one or morestereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentdisclosure. Cis and trans geometric isomers of the compounds of thepresent disclosure are described and may be isolated as a mixture ofisomers or as separated isomeric forms. In some embodiments, one or morecompounds depicted herein may exist in different tautomeric forms. Aswill be clear from context, unless explicitly excluded, references tosuch compounds encompass all such tautomeric forms. In some embodiments,tautomeric forms result from the swapping of a single bond with anadjacent double bond and the concomitant migration of a proton.

In certain embodiments, a tautomeric form may be a prototropic tautomer,which is an isomeric protonation states having the same empiricalformula and total charge as a reference form. Examples of moieties withprototropic tautomeric forms are ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Insome embodiments, tautomeric forms can be in equilibrium or stericallylocked into one form by appropriate substitution. In certainembodiments, tautomeric forms result from acetal interconversion.

As used herein, the term “degrader” refers to a small molecule compoundincluding a degradation moiety, wherein the compound interacts with aprotein (e.g., BRD9) in a way which results in degradation of theprotein, e.g., binding of the compound results in at least 5% reductionof the level of the protein, e.g., in a cell or subject.

As used herein, the term “degradation moiety” refers to a moiety whosebinding results in degradation of a protein, e.g., BRD9. In one example,the moiety binds to a protease or a ubiquitin ligase that metabolizesthe protein, e.g., BRD9.

By “determining the level of a protein” is meant the detection of aprotein, or an mRNA encoding the protein, by methods known in the arteither directly or indirectly. “Directly determining” means performing aprocess (e.g., performing an assay or test on a sample or “analyzing asample” as that term is defined herein) to obtain the physical entity orvalue. “Indirectly determining” refers to receiving the physical entityor value from another party or source (e.g., a third-party laboratorythat directly acquired the physical entity or value). Methods to measureprotein level generally include, but are not limited to, westernblotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surfaceplasmon resonance, chemiluminescence, fluorescent polarization,phosphorescence, immunohistochemical analysis, matrix-assisted laserdesorption/ionization time-of-flight (MALDI-TOF) mass spectrometry,liquid chromatography (LC)-mass spectrometry, microcytometry,microscopy, fluorescence activated cell sorting (FACS), and flowcytometry, as well as assays based on a property of a protein including,but not limited to, enzymatic activity or interaction with other proteinpartners. Methods to measure mRNA levels are known in the art.

As used herein, the terms “effective amount,” “therapeutically effectiveamount,” and “a “sufficient amount” of an agent that reduces the leveland/or activity of BRD9 (e.g., in a cell or a subject) described hereinrefer to a quantity sufficient to, when administered to the subject,including a human, effect beneficial or desired results, includingclinical results, and, as such, an “effective amount” or synonym theretodepends on the context in which it is being applied. For example, in thecontext of treating cancer, it is an amount of the agent that reducesthe level and/or activity of BRD9 sufficient to achieve a treatmentresponse as compared to the response obtained without administration ofthe agent that reduces the level and/or activity of BRD9. The amount ofa given agent that reduces the level and/or activity of BRD9 describedherein that will correspond to such an amount will vary depending uponvarious factors, such as the given agent, the pharmaceuticalformulation, the route of administration, the type of disease ordisorder, the identity of the subject (e.g., age, sex, and/or weight) orhost being treated, and the like, but can nevertheless be routinelydetermined by one of skill in the art. Also, as used herein, a“therapeutically effective amount” of an agent that reduces the leveland/or activity of BRD9 of the present disclosure is an amount whichresults in a beneficial or desired result in a subject as compared to acontrol. As defined herein, a therapeutically effective amount of anagent that reduces the level and/or activity of BRD9 of the presentdisclosure may be readily determined by one of ordinary skill by routinemethods known in the art. Dosage regimen may be adjusted to provide theoptimum therapeutic response.

As used herein, the term “inhibitor” refers to any agent which reducesthe level and/or activity of a protein (e.g., BRD9). Non-limitingexamples of inhibitors include small molecule inhibitors, degraders,antibodies, enzymes, or polynucleotides (e.g., siRNA).

The term “inhibitory RNA agent” refers to an RNA, or analog thereof,having sufficient sequence complementarity to a target RNA to direct RNAinterference. Examples also include a DNA that can be used to make theRNA. RNA interference (RNAi) refers to a sequence-specific or selectiveprocess by which a target molecule (e.g., a target gene, protein, orRNA) is down-regulated. Generally, an interfering RNA (“iRNA”) is adouble-stranded short-interfering RNA (siRNA), short hairpin RNA(shRNA), or single-stranded micro-RNA (miRNA) that results in catalyticdegradation of specific mRNAs, and also can be used to lower or inhibitgene expression.

By “level” is meant a level of a protein, or mRNA encoding the protein,as compared to a reference. The reference can be any useful reference,as defined herein. By a “decreased level” or an “increased level” of aprotein is meant a decrease or increase in protein level, as compared toa reference (e.g., a decrease or an increase by about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 100%, about 150%,about 200%, about 300%, about 400%, about 500%, or more; a decrease oran increase of more than about 10%, about 15%, about 20%, about 50%,about 75%, about 100%, or about 200%, as compared to a reference; adecrease or an increase by less than about 0.01-fold, about 0.02-fold,about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less;or an increase by more than about 1.2-fold, about 1.4-fold, about1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold,about 20-fold, about 30-fold, about 40-fold, about 50-fold, about100-fold, about 1000-fold, or more). A level of a protein may beexpressed in mass/vol (e.g., g/dL, mg/mL, μg/mL, ng/mL) or percentagerelative to total protein or mRNA in a sample.

The terms “miRNA” and “microRNA” refer to an RNA agent, preferably asingle-stranded agent, of about 10-50 nucleotides in length, preferablybetween about 15-25 nucleotides in length, which is capable of directingor mediating RNA interference. Naturally-occurring miRNAs are generatedfrom stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer. The term“Dicer” as used herein, includes Dicer as well as any Dicer ortholog orhomolog capable of processing dsRNA structures into siRNAs, miRNAs,siRNA-like or miRNA-like molecules. The term microRNA (“miRNA”) is usedinterchangeably with the term “small temporal RNA” (“stRNA”) based onthe fact that naturally-occurring miRNAs have been found to be expressedin a temporal fashion (e.g., during development).

By “modulating the activity of a BAF complex,” is meant altering thelevel of an activity related to a BAF complex (e.g., GBAF), or a relateddownstream effect. The activity level of a BAF complex may be measuredusing any method known in the art, e.g., the methods described in Kadochet al, Cell 153:71-85 (2013), the methods of which are hereinincorporated by reference.

“Percent (%) sequence identity” with respect to a referencepolynucleotide or polypeptide sequence is defined as the percentage ofnucleic acids or amino acids in a candidate sequence that are identicalto the nucleic acids or amino acids in the reference polynucleotide orpolypeptide sequence, after aligning the sequences and introducing gaps,if necessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent nucleic acid or amino acidsequence identity can be achieved in various ways that are within thecapabilities of one of skill in the art, for example, using publiclyavailable computer software such as BLAST, BLAST-2, or Megalignsoftware. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For example, percent sequence identity values may be generated using thesequence comparison computer program BLAST. As an illustration, thepercent sequence identity of a given nucleic acid or amino acidsequence, A, to, with, or against a given nucleic acid or amino acidsequence, B, (which can alternatively be phrased as a given nucleic acidor amino acid sequence, A that has a certain percent sequence identityto, with, or against a given nucleic acid or amino acid sequence, B) iscalculated as follows:

100 multiplied by (the fraction X/Y)

where X is the number of nucleotides or amino acids scored as identicalmatches by a sequence alignment program (e.g., BLAST) in that program'salignment of A and B, and where Y is the total number of nucleic acidsin B. It will be appreciated that where the length of nucleic acid oramino acid sequence A is not equal to the length of nucleic acid oramino acid sequence B, the percent sequence identity of A to B will notequal the percent sequence identity of B to A.

A “pharmaceutically acceptable excipient,” as used herein, refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being substantially nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, and waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A,vitamin E, vitamin C, and xylitol.

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of any of the compoundsdescribed herein. For example, pharmaceutically acceptable salts of anyof the compounds described herein include those that are within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and animals without undue toxicity, irritation,allergic response and are commensurate with a reasonable benefit/riskratio. Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during thefinal isolation and purification of the compounds described herein orseparately by reacting a free base group with a suitable organic acid.

The compounds described herein may have ionizable groups so as to becapable of preparation as pharmaceutically acceptable salts. These saltsmay be acid addition salts involving inorganic or organic acids or thesalts may, in the case of acidic forms of the compounds describedherein, be prepared from inorganic or organic bases. Frequently, thecompounds are prepared or used as pharmaceutically acceptable saltsprepared as addition products of pharmaceutically acceptable acids orbases. Suitable pharmaceutically acceptable acids and bases and methodsfor preparation of the appropriate salts are well-known in the art.Salts may be prepared from pharmaceutically acceptable non-toxic acidsand bases including inorganic and organic acids and bases.Representative acid addition salts include acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, and valeratesalts. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, andethylamine.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other pharmaceutically acceptable formulation.

By “reducing the activity of BRD9,” is meant decreasing the level of anactivity related to an BRD9, or a related downstream effect. Anon-limiting example of inhibition of an activity of BRD9 is decreasingthe level of a BAF complex (e.g., GBAF) in a cell. The activity level ofBRD9 may be measured using any method known in the art. In someembodiments, an agent which reduces the activity of BRD9 is a smallmolecule BRD9 inhibitor. In some embodiments, an agent which reduces theactivity of BRD9 is a small molecule BRD9 degrader.

By “reducing the level of BRD9,” is meant decreasing the level of BRD9in a cell or subject. The level of BRD9 may be measured using any methodknown in the art.

By a “reference” is meant any useful reference used to compare proteinor mRNA levels. The reference can be any sample, standard, standardcurve, or level that is used for comparison purposes. The reference canbe a normal reference sample or a reference standard or level. A“reference sample” can be, for example, a control, e.g., a predeterminednegative control value such as a “normal control” or a prior sampletaken from the same subject; a sample from a normal healthy subject,such as a normal cell or normal tissue; a sample (e.g., a cell ortissue) from a subject not having a disease; a sample from a subjectthat is diagnosed with a disease, but not yet treated with a compounddescribed herein; a sample from a subject that has been treated by acompound described herein; or a sample of a purified protein (e.g., anydescribed herein) at a known normal concentration. By “referencestandard or level” is meant a value or number derived from a referencesample. A “normal control value” is a pre-determined value indicative ofnon-disease state, e.g., a value expected in a healthy control subject.Typically, a normal control value is expressed as a range (“between Xand Y”), a high threshold (“no higher than X”), or a low threshold (“nolower than X”). A subject having a measured value within the normalcontrol value for a particular biomarker is typically referred to as“within normal limits” for that biomarker. A normal reference standardor level can be a value or number derived from a normal subject nothaving a disease or disorder (e.g., cancer); a subject that has beentreated with a compound described herein. In preferred embodiments, thereference sample, standard, or level is matched to the sample subjectsample by at least one of the following criteria: age, weight, sex,disease stage, and overall health. A standard curve of levels of apurified protein, e.g., any described herein, within the normalreference range can also be used as a reference.

The terms “short interfering RNA” and “siRNA” (also known as “smallinterfering RNAs”) refer to an RNA agent, preferably a double-strandedagent, of about 10-50 nucleotides in length, the strands optionallyhaving overhanging ends comprising, for example 1, 2 or 3 overhangingnucleotides (or nucleotide analogs), which is capable of directing ormediating RNA interference. Naturally-occurring siRNAs are generatedfrom longer dsRNA molecules (e.g., >25 nucleotides in length) by acell's RNAi machinery (e.g., Dicer or a homolog thereof).

The term “shRNA”, as used herein, refers to an RNA agent having astem-loop structure, comprising a first and second region ofcomplementary sequence, the degree of complementarity and orientation ofthe regions being sufficient such that base pairing occurs between theregions, the first and second regions being joined by a loop region, theloop resulting from a lack of base pairing between nucleotides (ornucleotide analogs) within the loop region.

As used herein, the term “subject” refers to any organism to which acomposition in accordance with the invention may be administered, e.g.,for experimental, diagnostic, prophylactic, and/or therapeutic purposes.Typical subjects include any animal (e.g., mammals such as mice, rats,rabbits, non-human primates, and humans). A subject may seek or be inneed of treatment, require treatment, be receiving treatment, bereceiving treatment in the future, or be a human or animal who is undercare by a trained professional for a particular disease or condition.

As used herein, the term “SS18-SSX fusion protein-related disorder”refers to a disorder that is caused or affected by the level and/oractivity of SS18-SSX fusion protein.

As used herein, the terms “treat,” “treated,” or “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms; diminishmentof the extent of a condition, disorder, or disease; stabilized (i.e.,not worsening) state of condition, disorder, or disease; delay in onsetor slowing of condition, disorder, or disease progression; ameliorationof the condition, disorder, or disease state or remission (whetherpartial or total), whether detectable or undetectable; an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient; or enhancement or improvement of condition,disorder, or disease. Treatment includes eliciting a clinicallysignificant response without excessive levels of side effects. Treatmentalso includes prolonging survival as compared to expected survival ifnot receiving treatment.

As used herein, the terms “variant” and “derivative” are usedinterchangeably and refer to naturally-occurring, synthetic, andsemi-synthetic analogues of a compound, peptide, protein, or othersubstance described herein. A variant or derivative of a compound,peptide, protein, or other substance described herein may retain orimprove upon the biological activity of the original material.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a series of graphs illustrating the effect of specific guideRNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovialsarcoma cell growth. The Y-axis indicated the dropout ratio. The X-axisindicates the nucleotide position of the BRD9 gene. The grey boxindicates the range of the negative control sgRNAs in the screen. TheSYO1 cell line carries SS18-SSX2 fusion protein. The breakpoint joiningthe N-terminal region of SS18 to the C-terminal region of SSX2 areindicated by the black lines in their respective panel. The linearprotein sequence is show with BRD9 PFAM domains annotated from the PFAMdatabase.

FIG. 2 is an image illustrating dose dependent depletion of BRD9 levelsin a synovial sarcoma cell line (SYO1) in the presence of a BRD9degrader.

FIG. 3 is an image illustrating sustained suppression of BRD9 levels ina synovial sarcoma cell line (SYO1) in the presence of a BRD9 degraderover 72 hours.

FIG. 4 is an image illustrating sustained suppression of BRD9 levels intwo cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5days.

FIG. 5 is an image illustrating sustained suppression of BRD9 levels insynovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9degrader over 7 days compared to the levels in cells treated with CRISPRreagents.

FIG. 6 is an image illustrating the effect on cell growth of six celllines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 293T) in the presence ofa BRD9 degrader and a BRD9 inhibitor.

FIG. 7 is an image illustrating the effect on cell growth of two celllines (SYO1 and G401) in the presence of a BRD9 degrader.

FIG. 8 is an image illustrating the effect on cell growth of threesynovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 9 is an image illustrating the effect on cell growth of threenon-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 10 is a graph illustrating the percentage of SYO1 in various cellcycle phases following treatment with DMSO, Compound 1 at 200 nM, orCompound 1 at 1 μM for 8 or 13 days.

FIG. 11 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 12 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for13 days. Numerical values corresponding to each contour plot are foundin the table below.

FIG. 13 is a series of contour plots illustrating the percentage ofearly- and late-apoptotic SYO1 cells following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 14 is a graph illustrating the proteins present in BAF complexesincluding the SS18-SSX fusion protein.

DETAILED DESCRIPTION

The present disclosure features compositions and methods useful for thetreatment of BAF-related disorders (e.g., cancer and infection). Thedisclosure further features compositions and methods useful forinhibition of the level and/or activity of BRD9, e.g., for the treatmentof disorders such as cancer (e.g., sarcoma) and infection (e.g., viralinfection), e.g., in a subject in need thereof.

Compounds

Compounds described herein reduce the level of an activity related toBRD9, or a related downstream effect, or reduce the level of BRD9 in acell or subject. Exemplary compounds described herein have the structureaccording to Formula I or Formula II.

Formula I is:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is N or CH, and X² is C—R⁷; or X¹ is C—R⁷, and X² is N or CH;

R⁷ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedamino, optionally substituted sulfone, optionally substitutedsulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms;

X³ is N or CH;

X⁴ is N or CH;

G is optionally substituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉heteroaryl, or a pharmaceutically acceptable salt thereof.

Formula II is:

A-L-B  Formula II,

where

L is a linker;

B is a degradation moiety; and

A has the structure of Formula III:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is N or CH, and X² is C—R^(7″); or X¹ is C—R^(7″), and X² is N or CH;

R^(7″) is

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedamino, optionally substituted sulfone, optionally substitutedsulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms;

R^(7′) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₁₀ carbocycylyl;

X³ is N or CH;

X⁴ is N or CH;

G″ is

optionally substituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉heteroaryl;

G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and

A¹ is a bond between A and the linker,

where G″ is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one ofcompounds B1-B6 in Table 1, or a pharmaceutically acceptable saltthereof

In some embodiments, the compound has the structure of any one ofcompounds D1-D31 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D32-D184 in Table 2B, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D185-D316 in Table 2C, or a pharmaceutically acceptablesalt thereof.

Other embodiments, as well as exemplary methods for the synthesis ofproduction of these compounds, are described herein.

Pharmaceutical Uses

The compounds described herein are useful in the methods of theinvention and, while not bound by theory, are believed to exert theirdesirable effects through their ability to modulate the level, status,and/or activity of a BAF complex, e.g., by inhibiting the activity orlevel of the BRD9 protein in a cell within the BAF complex in a mammal.

An aspect of the present invention relates to methods of treatingdisorders related to BRD9 such as cancer in a subject in need thereof.In some embodiments, the compound is administered in an amount and for atime effective to result in one of (or more, e.g., two or more, three ormore, four or more of): (a) reduced tumor size, (b) reduced rate oftumor growth, (c) increased tumor cell death (d) reduced tumorprogression, (e) reduced number of metastases, (f) reduced rate ofmetastasis, (g) decreased tumor recurrence (h) increased survival ofsubject, and (i) increased progression free survival of a subject.

Treating cancer can result in a reduction in size or volume of a tumor.For example, after treatment, tumor size is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto its size prior to treatment. Size of a tumor may be measured by anyreproducible means of measurement. For example, the size of a tumor maybe measured as a diameter of the tumor.

Treating cancer may further result in a decrease in number of tumors.For example, after treatment, tumor number is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto number prior to treatment. Number of tumors may be measured by anyreproducible means of measurement, e.g., the number of tumors may bemeasured by counting tumors visible to the naked eye or at a specifiedmagnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

Treating cancer can result in a decrease in number of metastatic nodulesin other tissues or organs distant from the primary tumor site. Forexample, after treatment, the number of metastatic nodules is reduced by5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% orgreater) relative to number prior to treatment. The number of metastaticnodules may be measured by any reproducible means of measurement. Forexample, the number of metastatic nodules may be measured by countingmetastatic nodules visible to the naked eye or at a specifiedmagnification (e.g., 2×, 10×, or 50×).

Treating cancer can result in an increase in average survival time of apopulation of subjects treated according to the present invention incomparison to a population of untreated subjects. For example, theaverage survival time is increased by more than 30 days (more than 60days, 90 days, or 120 days). An increase in average survival time of apopulation may be measured by any reproducible means. An increase inaverage survival time of a population may be measured, for example, bycalculating fora population the average length of survival followinginitiation of treatment with the compound described herein. An increasein average survival time of a population may also be measured, forexample, by calculating for a population the average length of survivalfollowing completion of a first round of treatment with apharmaceutically acceptable salt of a compound described herein.

Treating cancer can also result in a decrease in the mortality rate of apopulation of treated subjects in comparison to an untreated population.For example, the mortality rate is decreased by more than 2% (e.g., morethan 5%, 10%, or 25%). A decrease in the mortality rate of a populationof treated subjects may be measured by any reproducible means, forexample, by calculating for a population the average number ofdisease-related deaths per unit time following initiation of treatmentwith a pharmaceutically acceptable salt of a compound described herein.A decrease in the mortality rate of a population may also be measured,for example, by calculating for a population the average number ofdisease-related deaths per unit time following completion of a firstround of treatment with a pharmaceutically acceptable salt of a compounddescribed herein.

Combination Therapies

A method of the invention can be used alone or in combination with anadditional therapeutic agent, e.g., other agents that treat cancer orsymptoms associated therewith, or in combination with other types oftherapies to treat cancer. In combination treatments, the dosages of oneor more of the therapeutic compounds may be reduced from standarddosages when administered alone. For example, doses may be determinedempirically from drug combinations and permutations or may be deduced byisobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).In this case, dosages of the compounds when combined should provide atherapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeuticagent (e.g., a cytotoxic agent or other chemical compound useful in thetreatment of cancer). These include alkylating agents, antimetabolites,folic acid analogs, pyrimidine analogs, purine analogs and relatedinhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics,L-Asparaginase, topoisomerase inhibitors, interferons, platinumcoordination complexes, anthracenedione substituted urea, methylhydrazine derivatives, adrenocortical suppressant,adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens,antiandrogen, and gonadotropin-releasing hormone analog. Also includedis 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin,capecitabine, paclitaxel, and doxetaxel. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicinomegaII (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994));dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antiobiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin, including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®,cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum coordination complexes such as cisplatin, oxaliplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone;teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate;irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid;capecitabine; and pharmaceutically acceptable salts, acids orderivatives of any of the above. Two or more chemotherapeutic agents canbe used in a cocktail to be administered in combination with the firsttherapeutic agent described herein. Suitable dosing regimens ofcombination chemotherapies are known in the art and described in, forexample, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), andDouillard et al., Lancet 355(9209):1041-1047 (2000).

In some embodiments, the second therapeutic agent is a therapeutic agentwhich is a biologic such a cytokine (e.g., interferon or an interleukin(e.g., IL-2)) used in cancer treatment. In some embodiments the biologicis an anti-angiogenic agent, such as an anti-VEGF agent, e.g.,bevacizumab (AVASTIN®). In some embodiments the biologic is animmunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., ahumanized antibody, a fully human antibody, an Fc fusion protein or afunctional fragment thereof) that agonizes a target to stimulate ananti-cancer response, or antagonizes an antigen important for cancer.Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab);SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab);HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH®(alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab);XOLAIR® (omalizumab); BEXXAR® (tositumomab-I-131); RAPTIVA®(efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI®(natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab);LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumabpegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA®(ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX®(motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY®(ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab);KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Alsoincluded are antibody-drug conjugates.

The second agent may be a therapeutic agent which is a non-drugtreatment. For example, the second therapeutic agent is radiationtherapy, cryotherapy, hyperthermia, and/or surgical excision of tumortissue.

The second agent may be a checkpoint inhibitor. In one embodiment, theinhibitor of checkpoint is an inhibitory antibody (e.g., a monospecificantibody such as a monoclonal antibody). The antibody may be, e.g.,humanized or fully human. In some embodiments, the inhibitor ofcheckpoint is a fusion protein, e.g., an Fc-receptor fusion protein. Insome embodiments, the inhibitor of checkpoint is an agent, such as anantibody, that interacts with a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an agent, such as an antibody, thatinteracts with the ligand of a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4antibody or fusion a protein such as ipilimumab/YERVOY® ortremelimumab). In some embodiments, the inhibitor of checkpoint is aninhibitor (e.g., an inhibitory antibody or small molecule inhibitor) ofPD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®;pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint isan inhibitor (e.g., an inhibitory antibody or small molecule inhibitor)of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). Insome embodiments, the inhibitor of checkpoint is an inhibitor (e.g., aninhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2(e.g., a PDL2/Ig fusion protein such as AMP 224). In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4,BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1,CHK2, A2aR, B-7 family ligands, or a combination thereof.

In some embodiments, the anti-cancer therapy is a T cell adoptivetransfer (ACT) therapy. In some embodiments, the T cell is an activatedT cell. The T cell may be modified to express a chimeric antigenreceptor (CAR). CAR modified T (CAR-T) cells can be generated by anymethod known in the art. For example, the CAR-T cells can be generatedby introducing a suitable expression vector encoding the CAR to a Tcell. Prior to expansion and genetic modification of the T cells, asource of T cells is obtained from a subject. T cells can be obtainedfrom a number of sources, including peripheral blood mononuclear cells,bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from asite of infection, ascites, pleural effusion, spleen tissue, and tumors.In certain embodiments of the present invention, any number of T celllines available in the art, may be used. In some embodiments, the T cellis an autologous T cell. Whether prior to or after genetic modificationof the T cells to express a desirable protein (e.g., a CAR), the T cellscan be activated and expanded generally using methods as described, forexample, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964;5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869;7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; andU.S. Patent Application Publication No. 20060121005.

In any of the combination embodiments described herein, the first andsecond therapeutic agents are administered simultaneously orsequentially, in either order. The first therapeutic agent may beadministered immediately, up to 1 hour, up to 2 hours, up to 3 hours, upto 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours,up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours upto 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after thesecond therapeutic agent.

Pharmaceutical Compositions

The pharmaceutical compositions described herein are preferablyformulated into pharmaceutical compositions for administration to humansubjects in a biologically compatible form suitable for administrationin vivo.

The compounds described herein may be used in the form of the free base,in the form of salts, solvates, and as prodrugs. All forms are withinthe methods described herein. In accordance with the methods of theinvention, the described compounds or salts, solvates, or prodrugsthereof may be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds described herein may be administered,for example, by oral, parenteral, buccal, sublingual, nasal, rectal,patch, pump, intratumoral, or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal, and topical modes of administration. Parenteral administrationmay be by continuous infusion over a selected period of time.

A compound described herein may be orally administered, for example,with an inert diluent or with an assimilable edible carrier, or it maybe enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly with thefood of the diet. For oral therapeutic administration, a compounddescribed herein may be incorporated with an excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, and wafers. A compound described herein may also beadministered parenterally. Solutions of a compound described herein canbe prepared in water suitably mixed with a surfactant, such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, DMSO, and mixtures thereof with or withoutalcohol, and in oils. Under ordinary conditions of storage and use,these preparations may contain a preservative to prevent the growth ofmicroorganisms. Conventional procedures and ingredients for theselection and preparation of suitable formulations are described, forexample, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and inThe United States Pharmacopeia: The National Formulary (USP 41 NF36),published in 2018. The pharmaceutical forms suitable for injectable useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that may be easily administered via syringe. Compositions fornasal administration may conveniently be formulated as aerosols, drops,gels, and powders. Aerosol formulations typically include a solution orfine suspension of the active substance in a physiologically acceptableaqueous or non-aqueous solvent and are usually presented in single ormultidose quantities in sterile form in a sealed container, which cantake the form of a cartridge or refill for use with an atomizing device.Alternatively, the sealed container may be a unitary dispensing device,such as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve which is intended for disposal after use. Where thedosage form includes an aerosol dispenser, it will contain a propellant,which can be a compressed gas, such as compressed air or an organicpropellant, such as fluorochlorohydrocarbon. The aerosol dosage formscan also take the form of a pump-atomizer. Compositions suitable forbuccal or sublingual administration include tablets, lozenges, andpastilles, where the active ingredient is formulated with a carrier,such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositionsfor rectal administration are conveniently in the form of suppositoriescontaining a conventional suppository base, such as cocoa butter. Acompound described herein may be administered intratumorally, forexample, as an intratumoral injection. Intratumoral injection isinjection directly into the tumor vasculature and is specificallycontemplated for discrete, solid, accessible tumors. Local, regional, orsystemic administration also may be appropriate. A compound describedherein may advantageously be contacted by administering an injection ormultiple injections to the tumor, spaced for example, at approximately,1 cm intervals. In the case of surgical intervention, the presentinvention may be used preoperatively, such as to render an inoperabletumor subject to resection. Continuous administration also may beapplied where appropriate, for example, by implanting a catheter into atumor or into tumor vasculature.

The compounds described herein may be administered to an animal, e.g., ahuman, alone or in combination with pharmaceutically acceptablecarriers, as noted herein, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration, and standard pharmaceutical practice.

Dosages

The dosage of the compounds described herein, and/or compositionsincluding a compound described herein, can vary depending on manyfactors, such as the pharmacodynamic properties of the compound; themode of administration; the age, health, and weight of the recipient;the nature and extent of the symptoms; the frequency of the treatment,and the type of concurrent treatment, if any; and the clearance rate ofthe compound in the animal to be treated. One of skill in the art candetermine the appropriate dosage based on the above factors. Thecompounds described herein may be administered initially in a suitabledosage that may be adjusted as required, depending on the clinicalresponse. In general, satisfactory results may be obtained when thecompounds described herein are administered to a human at a daily dosageof, for example, between 0.05 mg and 3000 mg (measured as the solidform). Dose ranges include, for example, between 10-1000 mg (e.g.,50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of thecompound is administered.

Alternatively, the dosage amount can be calculated using the body weightof the patient. For example, the dose of a compound, or pharmaceuticalcomposition thereof, administered to a patient may range from 0.1-100mg/kg (e.g., 0.1-50 mg/kg (e.g., 0.25-25 mg/kg)). In exemplary,non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g.,0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

Kits

The invention also features kits including (a) a pharmaceuticalcomposition including an agent that reduces the level and/or activity ofBRD9 in a cell or subject described herein, and (b) a package insertwith instructions to perform any of the methods described herein. Insome embodiments, the kit includes (a) a pharmaceutical compositionincluding an agent that reduces the level and/or activity of BRD9 in acell or subject described herein, (b) an additional therapeutic agent(e.g., an anti-cancer agent), and (c) a package insert with instructionsto perform any of the methods described herein.

EXAMPLES Example 1—High Density Tiling sgRNA Screen Against Human BAFComplex Subunits in Synovial Sarcoma Cell Line SYO1

The following example shows that BRD9 sgRNA inhibits cell growth insynovial sarcoma cells.

Procedure:

To perform high density sgRNA tiling screen, an sgRNA library againstBAF complex subunits was custom synthesized at Cellecta (Mountain View,Calif.). Sequences of DNA encoding the BRD9-targeting sgRNAs used inthis screen are listed in Table 3. Negative and positive control sgRNAwere included in the library. Negative controls consisted of 200 sgRNAsthat do not target human genome. The positive controls are sgRNAstargeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA,POLR2L, RPL9, and SF3A3). DNA sequences encoding all positive andnegative control sgRNAs are listed in Table 4. Procedures for virusproduction, cell infection, and performing the sgRNA screen werepreviously described (Tsherniak et al, Cell 170:564-576 (2017); Munoz etal, Cancer Discovery 6:900-913 (2016)). For each sgRNA, 50 counts wereadded to the sequencing counts and for each time point the resultingcounts were normalized to the total number of counts. The log 2 of theratio between the counts (defined as dropout ratio) at day 24 and day 1post-infection was calculated. For negative control sgRNAs, the 2.5 and97.5 percentile of the log 2 dropout ratio of all non-targeting sgRNAswas calculated and considered as background (grey box in the graph).Protein domains were obtained from PFAM regions defined for the UNIPROTidentifier: Q9H8M2.

Results:

As shown in FIG. 1 , targeted inhibition of the GBAF complex componentBRD9 by sgRNA resulted in growth inhibition of the SYO1 synovial sarcomacell line. sgRNAs against other components of the BAF complexes resultedin increased proliferation of cells, inhibition of cell growth, or hadno effect on SYO1 cells. These data show that targeting various subunitsof the GBAF complex represents a therapeutic strategy for the treatmentof synovial sarcoma.

TABLE 3 BRD9 sgRNA Library SEQ ID NO Nucleic Acid Sequence 203CAAGAAGCACAAGAAGCACA 204 CTTGTGCTTCTTGCCCATGG 205 CTTCTTGTGCTTCTTGCCCA206 ACAAGAAGCACAAGGCCGAG 207 CTCGTAGGACGAGCGCCACT 208CGAGTGGCGCTCGTCCTACG 209 GAGTGGCGCTCGTCCTACGA 210 AGGCTTCTCCAGGGGCTTGT211 AGATTATGCCGACAAGCCCC 212 ACCTTCAGGACTAGCTTTAG 213AGCTTTAGAGGCTTCTCCAG 214 CTAGCTTTAGAGGCTTCTCC 215 TAGCTTTAGAGGCTTCTCCA216 CTAAAGCTAGTCCTGAAGGT 217 GCCTCTAAAGCTAGTCCTGA 218CTTCACTTCCTCCGACCTTC 219 AAGCTAGTCCTGAAGGTCGG 220 AGTGAAGTGACTGAACTCTC221 GTGACTGAACTCTCAGGATC 222 ATAGTAACTGGAGTCGTGGC 223CATCATAGTAACTGGAGTCG 224 TGACCTGTCATCATAGTAAC 225 ACTCCAGTTACTATGATGAC226 CTTTGTGCCTCTCTCGCTCA 227 GGTCAGACCATGAGCGAGAG 228GAAGAAGAAGAAGTCCGAGA 229 GTCCAGATGCTTCTCCTTCT 230 GTCCGAGAAGGAGAAGCATC231 GGAGAAGCATCTGGACGATG 232 TGAGGAAAGAAGGAAGCGAA 233ATCTGGACGATGAGGAAAGA 234 AGAAGAAGCGGAAGCGAGAG 235 GAAGAAGCGGAAGCGAGAGA236 CCGCCCAGGAAGAGAAGAAG 237 AGAGAGGGAGCACTGTGACA 238AGGGAGCACTGTGACACGGA 239 GAGGGAGCACTGTGACACGG 240 GCACTGTGACACGGAGGGAG241 GAGGCTGACGACTTTGATCC 242 AGGCTGACGACTTTGATCCT 243TCCACCTCCACCTTCTTCCC 244 CGACTTTGATCCTGGGAAGA 245 CTTTGATCCTGGGAAGAAGG246 TGATCCTGGGAAGAAGGTGG 247 TCCTGGGAAGAAGGTGGAGG 248CGGACTGGCCGATCTGGGGG 249 ACGCTCGGACTGGCCGATCT 250 AGGTGGAGCCGCCCCCAGAT251 CGCTCGGACTGGCCGATCTG 252 GCTCGGACTGGCCGATCTGG 253CACGCTCGGACTGGCCGATC 254 TGTGTCCGGCACGCTCGGAC 255 CTGGCTGTGTCCGGCACGCT256 ATCGGCCAGTCCGAGCGTGC 257 CACCCTTGCCTGGCTGTGTC 258CGAGCGTGCCGGACACAGCC 259 TGTTCCAGGAGTTGCTGAAT 260 CACACCTATTCAGCAACTCC261 GCTGGCGGAGGAAGTGTTCC 262 TTTACCTCTGAAGCTGGCGG 263CCCCGGTTTACCTCTGAAGC 264 ACTTCCTCCGCCAGCTTCAG 265 CAGGAAAAGCAAAAAATCCA266 GCTTTCAGAAAAGATCCCCA 267 AGGAAAAGCAAAAAATCCAT 268GGAAAAGCAAAAAATCCATG 269 GGAGCAATTGCATCCGTGAC 270 GTCACGGATGCAATTGCTCC271 TTTATTATCATTGAATATCC 272 AATGATAATAAAACATCCCA 273ATAAAACATCCCATGGATTT 274 TTCATGGTGCCAAAATCCAT 275 TTTCATGGTGCCAAAATCCA276 TAATGAATACAAGTCAGTTA 277 CAAGTCAGTTACGGAATTTA 278ATAATGCAATGACATACAAT 279 AACTTGTAGTACACGGTATC 280 CTTCGCCAACTTGTAGTACA281 AGATACCGTGTACTACAAGT 282 GCGAAGAAGATCCTTCACGC 283TCATCTTAAAGCCTGCGTGA 284 TTCTCAGCAGGCAGCTCTTT 285 CAATGAAGATACAGCTGTTG286 ACTGGTACAACTTCAGGGAC 287 CTTGTACTGGTACAACTTCA 288ACTTGTACTGGTACAACTTC 289 TTGGCAGTTTCTACTTGTAC 290 TACCTGATAACTTCTCTACT291 AGCCGAGTAGAGAAGTTATC 292 AGCTGCATGTTTGAGCCTGA 293GCTGCATGTTTGAGCCTGAA 294 AAGCTGCAGGCATTCCCTTC 295 GGTACTGTCCGTCAAGCTGC296 AGGGAATGCCTGCAGCTTGA 297 CTTGACGGACAGTACCGCAG 298CGCCAGCACGTGCTCCTCTG 299 TACCGCAGAGGAGCACGTGC 300 AGAGGAGCACGTGCTGGCGC301 GGAGCACGTGCTGGCGCTGG 302 AGCACGCAGCTGACGAAGCT 303GCACGCAGCTGACGAAGCTC 304 CAGCTGACGAAGCTCGGGAC 305 AAGCTCGGGACAGGATCAAC306 CCTTGCCGCCTGGGAGGAAC 307 AGGATCAACCGGTTCCTCCC 308ATCAACCGGTTCCTCCCAGG 309 GCACTACCTTGCCGCCTGGG 310 AGAGCACTACCTTGCCGCCT311 CCGGTTCCTCCCAGGCGGCA 312 TCCTCTTCAGATAGCCCATC 313ATGGGCTATCTGAAGAGGAA 314 GGGCTATCTGAAGAGGAACG 315 TGGGCTATCTGAAGAGGAAC316 TATCTGAAGAGGAACGGGGA 317 ATCTGAAGAGGAACGGGGAC 318TGTTGACCACGCTGTAGAGC 319 GCTCTACAGCGTGGTCAACA 320 CGGGAGCCTGCTCTACAGCG321 CGTGGTCAACACGGCCGAGC 322 CCCACCATCAGCGTCCGGCT 323ACGGCCGAGCCGGACGCTGA 324 GGGCACCCACCATCAGCGTC 325 GCCGAGCCGGACGCTGATGG326 CCATGTCCGTGTTGCAGAGG 327 CCGAGCCGGACGCTGATGGT 328CGAGCTCAAGTCCACCGGGT 329 GCGAGCTCAAGTCCACCGGG 330 AGAGCGAGCTCAAGTCCACC331 GAGAGCGAGCTCAAGTCCAC 332 GAAGCCTGGGAGTAGCTTAC 333CTCTCCAGTAAGCTACTCCC 334 AGCCCAGCGTGGTGAAGCCT 335 AAGCCCAGCGTGGTGAAGCC336 ACTCCCAGGCTTCACCACGC 337 CTCCCAGGCTTCACCACGCT 338CTCGTCTTTGAAGCCCAGCG 339 CACTGGAGAGAAAGGTGACT 340 GCACTGGAGAGAAAGGTGAC341 AGTAGTGGCACTGGAGAGAA 342 CGAAAGCGCAGTAGTGGCAC 343CTGCATCGAAAGCGCAGTAG 344 ATGCAGAATAATTCAGTATT 345 AGTATTTGGCGACTTGAAGT346 CGACTTGAAGTCGGACGAGA 347 GAGCTGCTCTACTCAGCCTA 348CACGCCTGTCTCATCTCCGT 349 TCAGCCTACGGAGATGAGAC 350 CAGGCGTGCAGTGTGCGCTG351 CCGCGGCCCCTCTAGCCTGC 352 CATCCTTCACAAACTCCTGC 353TAGCCTGCAGGAGTTTGTGA 354 CAGGAGTTTGTGAAGGATGC 355 AGGAGTTTGTGAAGGATGCT356 TGGGAGCTACAGCAAGAAAG 357 GAGCTACAGCAAGAAAGTGG 358GAAAGTGGTGGACGACCTCC 359 CGCCTGTGATCTGGTCCAGG 360 CTCCGCCTGTGATCTGGTCC361 GACCTCCTGGACCAGATCAC 362 CTCCTGGACCAGATCACAGG 363GCTGGAAGAGCGTCCTAGAG 364 TGCAGCCCACCTGCTTCAGC 365 GACGCTCTTCCAGCTGAAGC366 CTCTTCCAGCTGAAGCAGGT 367 GCTCTTCCAGCTGAAGCAGG 368CCTCCAGATGAAGCCAAGGT 369 GCTTCATCTGGAGGCTTCAT 370 GGCTTCATCTGGAGGCTTCA371 CTTACCTTGGCTTCATCTGG 372 AAACTTACCTTGGCTTCATC 373GAAGCCTCCAGATGAAGCCA 374 TCCTAGGGTGTCCCCAACCT 375 CCTAGGGTGTCCCCAACCTG376 GTGTCTGTCTCCACAGGTTG 377 TGTGTCTGTCTCCACAGGTT 378CCACAGGTTGGGGACACCCT 379 AGAGCTGCTGCTGTCTCCTA 380 CAGAGCTGCTGCTGTCTCCT381 AGACAGCAGCAGCTCTGTTC 382 ATCCACAGAAACGTCGGGAT 383GAGATATCCACAGAAACGTC 384 GGAGATATCCACAGAAACGT 385 GTCCTATCCCGACGTTTCTG386 TCTCCATGCTCAGCTCTCTG 387 CTCACCCAGAGAGCTGAGCA 388ATCTCCATGCTCAGCTCTCT 389 TATCTCCATGCTCAGCTCTC 390 ATGTCCTGTTTACACAGGGA391 TTACACAGGGAAGGTGAAGA 392 AGTTCAAATGGCTGTCGTCA 393TGACGACAGCCATTTGAACT 394 AAGTTCAAATGGCTGTCGTC 395 TCGTCTCATCCAAGTTCAAA396 TGAGACGACGAAGCTCCTGC 397 GTGCTTCGTGCAGGTCCTGC 398GCAGGACCTGCACGAAGCAC 399 GCTCCGCCTGTGCTTCGTGC 400 GGACCTGCACGAAGCACAGG401 CACGAAGCACAGGCGGAGCG 402 AGGCGGAGCGCGGCGGCTCT 403AGGGAGCTGAGGTTGGACGA 404 GTTGGACAGGGAGCTGAGGT 405 AGGCGTTGGACAGGGAGCTG406 CCCTCTCGGAGGCGTTGGAC 407 CCTCTCGGAGGCGTTGGACA 408CTGGTCCCTCTCGGAGGCGT 409 CCCTGTCCAACGCCTCCGAG 410 CCTGTCCAACGCCTCCGAGA411 GTGGTGCTGGTCCCTCTCGG 412 CAGGTGGTGCTGGTCCCTCT 413GCATCTCACCCAGGTGGTGC 414 CGAGAGGGACCAGCACCACC 415 GAGAGGGACCAGCACCACCT416 GTGGGGGCATCTCACCCAGG 417 CCCCGACACTCAGGCGAGAA 418TCCCCGACACTCAGGCGAGA 419 AGCCCTTCTCGCCTGAGTGT 420 CTGGCTGCTCCCCGACACTC421 CCCTTCTCGCCTGAGTGTCG 422 GCCCTTCTCGCCTGAGTGTC 423TAGGGGTCGTGGGTGACGTC 424 AAGAAACTCATAGGGGTCGT 425 GAAGAAACTCATAGGGGTCG426 GAGACTGAAGAAACTCATAG 427 GGAGACTGAAGAAACTCATA 428TGGAGACTGAAGAAACTCAT 429 TCTTCAGTCTCCAGAGCCTG 430 TTGGCAGAGGCCGCAGGCTC431 TAGGTCTTGGCAGAGGCCGC 432 CTAGAGTTAGGTCTTGGCAG 433GGTGGTCTAGAGTTAGGTCT

TABLE 4 Control sgRNA Library SEQ ID NO. gRNA Label GeneNucleic Acid Sequence 434 1|sg_Non_Targeting_ Non_Targeting_HumanGTAGCGAACGTGTCCGGCGT Human_0001|Non_Targeting_ Human 4351|sg_Non_Targeting_ Non_Targeting_Human GACCGGAACGATCTCGCGTAHuman_0002|Non_Targeting_ Human 436 1|sg_Non_Targeting_Non_Targeting_Human GGCAGTCGTTCGGTTGATAT Human_0003|Non_Targeting_ Human437 1|sg_Non_Targeting_ Non_Targeting_Human GCTTGAGCACATACGCGAATHuman_0004|Non_Targeting_ Human 438 1|sg_Non_Targeting_Non_Targeting_Human GTGGTAGAATAACGTATTAC Human_0005|Non_Targeting_ Human439 1|sg_Non_Targeting_ Non_Targeting_Human GTCATACATGGATAAGGCTAHuman_0006|Non_Targeting_ Human 440 1|sg_Non_Targeting_Non_Targeting_Human GATACACGAAGCATCACTAG Human_0007|Non_Targeting_ Human441 1|sg_Non_Targeting_ Non_Targeting_Human GAACGTTGGCACTACTTCACHuman_0008|Non_Targeting_ Human 442 1|sg_Non_Targeting_Non_Targeting_Human GATCCATGTAATGCGTTCGA Human_0009|Non_Targeting_ Human443 1|sg_Non_Targeting_ Non_Targeting_Human GTCGTGAAGTGCATTCGATCHuman_0010|Non_Targeting_ Human 444 1|sg_Non_Targeting_Non_Targeting_Human GTTCGACTCGCGTGACCGTA Human_0011|Non_Targeting_ Human445 1|sg_Non_Targeting_ Non_Targeting_Human GAATCTACCGCAGCGGTTCGHuman_0012|Non_Targeting_ Human 446 1|sg_Non_Targeting_Non_Targeting_Human GAAGTGACGTCGATTCGATA Human_0013|Non_Targeting_ Human447 1|sg_Non_Targeting_ Non_Targeting_Human GCGGTGTATGACAACCGCCGHuman_0014|Non_Targeting_ Human 448 1|sg_Non_Targeting_Non_Targeting_Human GTACCGCGCCTGAAGTTCGC Human_0015|Non_Targeting_ Human449 1|sg_Non_Targeting_ Non_Targeting_Human GCAGCTCGTGTGTCGTACTCHuman_0016|Non_Targeting_ Human 450 1|sg_Non_Targeting_Non_Targeting_Human GCGCCTTAAGAGTACTCATC Human_0017|Non_Targeting_ Human451 1|sg_Non_Targeting_ Non_Targeting_Human GAGTGTCGTCGTTGCTCCTAHuman_0018|Non_Targeting_ Human 452 1|sg_Non_Targeting_Non_Targeting_Human GCAGCTCGACCTCAAGCCGT Human_0019|Non_Targeting_ Human453 1|sg_Non_Targeting_ Non_Targeting_Human GTATCCTGACCTACGCGCTGHuman_0020|Non_Targeting_ Human 454 1|sg_Non_Targeting_Non_Targeting_Human GTGTATCTCAGCACGCTAAC Human_0021I|Non_Targeting_Human 455 1|sg_Non_Targeting_ Non_Targeting_Human GTCGTCATACAACGGCAACGHuman_0022|Non_Targeting_ Human 456 1|sg_Non_Targeting_Non_Targeting_Human GTCGTGCGCTTCCGGCGGTA Human_0023-51 Non_Targeting_Human 457 1|sg_Non_Targeting_ Non_Targeting_Human GCGGTCCTCAGTAAGCGCGTHuman_0024|Non_Targeting_ Human 458 1|sg_Non_Targeting_Non_Targeting_Human GCTCTGCTGCGGAAGGATTC Human_0025|Non_Targeting_ Human459 1|sg_Non_Targeting_ Non_Targeting_Human GCATGGAGGAGCGTCGCAGAHuman_0026|Non_Targeting_ Human 460 1|sg_Non_Targeting_Non_Targeting_Human GTAGCGCGCGTAGGAGTGGC Human_0027|Non_Targeting_ Human461 1|sg_Non_Targeting_ Non_Targeting_Human GATCACCTGCATTCGTACACHuman_0028|Non_Targeting_ Human 462 1|sg_Non_Targeting_Non_Targeting_Human GCACACCTAGATATCGAATG Human_0029|Non_Targeting_ Human463 1|sg_Non_Targeting_ Non_Targeting_Human GTTGATCAACGCGCTTCGCGHuman_0030|Non_Targeting_ Human 464 1|sg_Non_Targeting_Non_Targeting_Human GCGTCTCACTCACTCCATCG Human_0031|Non_Targeting_ Human465 1|sg_Non_Targeting_ Non_Targeting_Human GCCGACCAACGTCAGCGGTAHuman_0032|Non_Targeting_ Human 466 1|sg_Non_Targeting_Non_Targeting_Human GGATACGGTGCGTCAATCTA Human_0033|Non_Targeting_ Human467 1|sg_Non_Targeting_ Non_Targeting_Human GAATCCAGTGGCGGCGACAAHuman_0034|Non_Targeting_ Human 468 1|sg_Non_Targeting_Non_Targeting_Human GCACTGTCAGTGCAACGATA Human_0035|Non_Targeting_ Human469 1|sg_Non_Targeting_ Non_Targeting_Human GCGATCCTCAAGTATGCTCAHuman_0036|Non_Targeting_ Human 470 1|sg_Non_Targeting_Non_Targeting_Human GCTAATATCGACACGGCCGC Human_0037|Non_Targeting_ Human471 1|sg_Non_Targeting_ Non_Targeting_Human GGAGATGCATCGAAGTCGATHuman_0038|Non_Targeting_ Human 472 1|sg_Non_Targeting_Non_Targeting_Human GGATGCACTCCATCTCGTCT Human_0039|Non_Targeting_ Human473 1|sg_Non_Targeting_ Non_Targeting_Human GTGCCGAGTAATAACGCGAGHuman_0040|Non_Targeting_ Human 474 1|sg_Non_Targeting_Non_Targeting_Human GAGATTCCGATGTAACGTAC Human_0041|Non_Targeting_ Human475 1|sg_Non_Targeting_ Non_Targeting_Human GTCGTCACGAGCAGGATTGCHuman_0042|Non_Targeting_ Human 476 1|sg_Non_Targeting_Non_Targeting_Human GCGTTAGTCACTTAGCTCGA Human_0043|Non_Targeting_ Human477 1|sg_Non_Targeting_ Non_Targeting_Human GTTCACACGGTGTCGGATAGHuman_0044|Non_Targeting_ Human 478 1|sg_Non_Targeting_Non_Targeting_Human GGATAGGTGACCTTAGTACG Human_0045|Non_Targeting_ Human479 1|sg_Non_Targeting_ Non_Targeting_Human GTATGAGTCAAGCTAATGCGHuman_0046|Non_Targeting_ Human 480 1|sg_Non_Targeting_Non_Targeting_Human GCAACTATTGGAATACGTGA Human_0047|Non_Targeting_ Human481 1|sg_Non_Targeting_ Non_Targeting_Human GTTACCTTCGCTCGTCTATAHuman_0048|Non_Targeting_ Human 482 1|sg_Non_Targeting_Non_Targeting_Human GTACCGAGCACCACAGGCCG Human_0049|Non_Targeting_ Human483 1|sg_Non_Targeting_ Non_Targeting_Human GTCAGCCATCGGATAGAGATHuman_0050|Non_Targeting_ Human 484 1|sg_Non_Targeting_Non_Targeting_Human GTACGGCACTCCTAGCCGCT Human_0051|Non_Targeting_ Human485 1|sg_Non_Targeting_ Non_Targeting_Human GGTCCTGTCGTATGCTTGCAHuman_0052|Non_Targeting_ Human 486 1|sg_Non_Targeting_Non_Targeting_Human GCCGCAATATATGCGGTAAG Human_0053|Non_Targeting_ Human487 1|sg_Non_Targeting_ Non_Targeting_Human GCGCACGTATAATCCTGCGTHuman_0054|Non_Targeting_ Human 488 1|sg_Non_Targeting_Non_Targeting_Human GTGCACAACACGATCCACGA Human_0055|Non_Targeting_ Human489 1|sg_Non_Targeting_ Non_Targeting_Human GCACAATGTTGACGTAAGTGHuman_0056|Non_Targeting_ Human 490 1|sg_Non_Targeting_Non_Targeting_Human GTAAGATGCTGCTCACCGTG Human_0057|Non_Targeting_ Human491 1|sg_Non_Targeting_ Non_Targeting_Human GTCGGTGATCCAACGTATCGHuman_0058|Non_Targeting_ Human 492 1|sg_Non_Targeting_Non_Targeting_Human GAGCTAGTAGGACGCAAGAC Human_0059|Non_Targeting_ Human493 1|sg_Non_Targeting_ Non_Targeting_Human GTACGTGGAAGCTTGTGGCCHuman_0060|Non_Targeting_ Human 494 1|sg_Non_Targeting_Non_Targeting_Human GAGAACTGCCAGTTCTCGAT Human_0061|Non_Targeting_ Human495 1|sg_Non_Targeting_ Non_Targeting_Human GCCATTCGGCGCGGCACTTCHuman_0062|Non_Targeting_ Human 496 1|sg_Non_Targeting_Non_Targeting_Human GCACACGACCAATCCGCTTC Human_0063|Non_Targeting_ Human497 1|sg_Non_Targeting_ Non_Targeting_Human GAGGTGATCGATTAAGTACAHuman_0064|Non_Targeting_ Human 498 1|sg_Non_Targeting_Non_Targeting_Human GTCACTCGCAGACGCCTAAC Human_0065|Non_Targeting_ Human499 1|sg_Non_Targeting_ Non_Targeting_Human GCGCTACGGAATCATACGTTHuman_0066|Non_Targeting_ Human 500 1|sg_Non_Targeting_Non_Targeting_Human GGTAGGACCTCACGGCGCGC Human_0067|Non_Targeting_ Human501 1|sg_Non_Targeting_ Non_Targeting_Human GAACTGCATCTTGTTGTAGTHuman_0068|Non_Targeting_ Human 502 1|sg_Non_Targeting_Non_Targeting_Human GATCCTGATCCGGCGGCGCG Human_0069|Non_Targeting_ Human503 1|sg_Non_Targeting_ Non_Targeting_Human GGTATGCGCGATCCTGAGTTHuman_0070|Non_Targeting_ Human 504 1|sg_Non_Targeting_Non_Targeting_Human GCGGAGCTAGAGAGCGGTCA Human_0071|Non_Targeting_ Human505 1|sg_Non_Targeting_ Non_Targeting_Human GAATGGCAATTACGGCTGATHuman_0072|Non_Targeting_ Human 506 1|sg_Non_Targeting_Non_Targeting_Human GTATGGTGAGTAGTCGCTTG Human_0073|Non_Targeting_ Human507 1|sg_Non_Targeting_ Non_Targeting_Human GTGTAATTGCGTCTAGTCGGHuman_0074|Non_Targeting_ Human 508 1|sg_Non_Targeting_Non_Targeting_Human GGTCCTGGCGAGGAGCCTTG Human_0075|Non_Targeting_ Human509 1|sg_Non_Targeting_ Non_Targeting_Human GAAGATAAGTCGCTGTCTCGHuman_0076|Non_Targeting_ Human 510 1|sg_Non_Targeting_Non_Targeting_Human GTCGGCGTTCTGTTGTGACT Human_0077|Non_Targeting_ Human511 1|sg_Non_Targeting_ Non_Targeting_Human GAGGCAAGCCGTTAGGTGTAHuman_0078|Non_Targeting_ Human 512 1|sg_Non_Targeting_Non_Targeting_Human GCGGATCCAGATCTCATTCG Human_0079|Non_Targeting_ Human513 1|sg_Non_Targeting_ Non_Targeting_Human GGAACATAGGAGCACGTAGTHuman_0080|Non_Targeting_ Human 514 1|sg_Non_Targeting_Non_Targeting_Human GTCATCATTATGGCGTAAGG Human_0081|Non_Targeting_ Human515 1|sg_Non_Targeting_ Non_Targeting_Human GCGACTAGCGCCATGAGCGGHuman_0082|Non_Targeting_ Human 516 1|sg_Non_Targeting_Non_Targeting_Human GGCGAAGTTCGACATGACAC Human_0083|Non_Targeting_ Human517 1|sg_Non_Targeting_ Non_Targeting_Human GCTGTCGTGTGGAGGCTATGHuman_0084|Non_Targeting_ Human 518 1|sg_Non_Targeting_Non_Targeting_Human GCGGAGAGCATTGACCTCAT Human_0085|Non_Targeting_ Human519 1|sg_Non_Targeting_ Non_Targeting_Human GACTAATGGACCAAGTCAGTHuman_0086|Non_Targeting_ Human 520 1|sg_Non_Targeting_Non_Targeting_Human GCGGATTAGAGGTAATGCGG Human_0087|Non_Targeting_ Human521 1|sg_Non_Targeting_ Non_Targeting_Human GCCGACGGCAATCAGTACGCHuman_0088|Non_Targeting_ Human 522 1|sg_Non_Targeting_Non_Targeting_Human GTAACCTCTCGAGCGATAGA Human_0089|Non_Targeting_ Human523 1|sg_Non_Targeting_ Non_Targeting_Human GACTTGTATGTGGCTTACGGHuman_0090|Non_Targeting_ Human 524 1|sg_Non_Targeting_Non_Targeting_Human GTCACTGTGGTCGAACATGT Human_0091|Non_Targeting_ Human525 1|sg_Non_Targeting_ Non_Targeting_Human GTACTCCAATCCGCGATGACHuman_0092|Non_Targeting_ Human 526 1|sg_Non_Targeting_Non_Targeting_Human GCGTTGGCACGATGTTACGG Human_0093|Non_Targeting_ Human527 1|sg_Non_Targeting_ Non_Targeting_Human GAACCAGCCGGCTAGTATGAHuman_0094|Non_Targeting_ Human 528 1|sg_Non_Targeting_Non_Targeting_Human GTATACTAGCTAACCACACG Human_0095|Non_Targeting_ Human529 1|sg_Non_Targeting_ Non_Targeting_Human GAATCGGAATAGTTGATTCGHuman_0096|Non_Targeting_ Human 530 1|sg_Non_Targeting_Non_Targeting_Human GAGCACTTGCATGAGGCGGT Human_0097|Non_Targeting_ Human531 1|sg_Non_Targeting_ Non_Targeting_Human GAACGGCGATGAAGCCAGCCHuman_0098|Non_Targeting_ Human 532 1|sg_Non_Targeting_Non_Targeting_Human GCAACCGAGATGAGAGGTTC Human_0099|Non_Targeting_ Human533 1|sg_Non_Targeting_ Non_Targeting_Human GCAAGATCAATATGCGTGATHuman_0100|Non_Targeting_ Human 534 1|sg_Non_Targeting_Non_Targeting_Human ACGGAGGCTAAGCGTCGCAA Human_GA_0101|Non_Targeting_Human 535 1|sg_Non_Targeting_ Non_Targeting_Human CGCTTCCGCGGCCCGTTCAAHuman_GA_0102|Non_Targeting_ Human 536 1|sg_Non_Targeting_Non_Targeting_Human ATCGTTTCCGCTTAACGGCG Human_GA_0103|Non_Targeting_Human 537 1|sg_Non_Targeting_ Non_Targeting_Human GTAGGCGCGCCGCTCTCTACHuman_GA_0104|Non_Targeting_ Human 538 1|sg_Non_Targeting_Non_Targeting_Human CCATATCGGGGCGAGACATG Human_GA_0105|Non_Targeting_Human 539 1|sg_Non_Targeting_ Non_Targeting_Human TACTAACGCCGCTCCTACAGHuman_GA_0106|Non_Targeting_ Human 540 1|sg_Non_Targeting_Non_Targeting_Human TGAGGATCATGTCGAGCGCC Human_GA_0107|Non_Targeting_Human 541 1|sg_Non_Targeting_ Non_Targeting_Human GGGCCCGCATAGGATATCGCHuman_GA_0108|Non_Targeting_ Human 542 1|sg_Non_Targeting_Non_Targeting_Human TAGACAACCGCGGAGAATGC Human_GA_0109|Non_Targeting_Human 543 1|sg_Non_Targeting_ Non_Targeting_Human ACGGGCGGCTATCGCTGACTHuman_GA_0110|Non_Targeting_ Human 544 1|sg_Non_Targeting_Non_Targeting_Human CGCGGAAATTTTACCGACGA Human_GA_0111|Non_Targeting_Human 545 1|sg_Non_Targeting_ Non_Targeting_Human CTTACAATCGTCGGTCCAATHuman_GA_0112|Non_Targeting_ Human 546 1|sg_Non_Targeting_Non_Targeting_Human GCGTGCGTCCCGGGTTACCC Human_GA_0113|Non_Targeting_Human 547 1|sg_Non_Targeting_  Non_Targeting_Human CGGAGTAACAAGCGGACGGAHuman_GA_0114|Non_Targeting_ Human 548 1|sg_Non_Targeting_Non_Targeting_Human CGAGTGTTATACGCACCGTT Human_GA_0115|Non_Targeting_Human 549 1|sg_Non_Targeting_ Non_Targeting_Human CGACTAACCGGAAACTTTTTHuman_GA_0116|Non_Targeting_ Human 550 1|sg_Non_Targeting_Non_Targeting_Human CAACGGGTTCTCCCGGCTAC Human_GA_0117|Non_Targeting_Human 551 1|sg_Non_Targeting_ Non_Targeting_Human CAGGAGTCGCCGATACGCGTHuman_GA_0118|Non_Targeting_ Human 552 1|sg_Non_Targeting_Non_Targeting_Human TTCACGTCGTCTCGCGACCA Human_GA_0119|Non_Targeting_Human 553 1|sg_Non_Targeting_ Non_Targeting_Human GTGTCGGATTCCGCCGCTTAHuman_GA_0120|Non_Targeting_ Human 554 1|sg_Non_Targeting_Human_GA_0121|Non_Targeting_ Non_Targeting_Human CACGAACTCACACCGCGCGAHuman 555 1|sg_Non_Targeting_ Human_GA_0122|Non_Targeting_Non_Targeting_Human CGCTAGTACGCTCCTCTATA Human 556 1|sg_Non_Targeting_Human_GA_0123|Non_Targetng_i Non_Targeting_Human TCGCGCTTGGGTTATACGCTHuman 557 1|sg_Non_Targeting_ Human_GA_0124|Non_Targeting_Non_Targeting_Human CTATCTCGAGTGGTAATGCG Human 558 1|sg_Non_Targeting_Human_GA_0125|Non_Targeting_ Non_Targeting_Human AATCGACTCGAACTTCGTGTHuman 559 1|sg_Non_Targeting_ Human_GA_0126|Non_Targeting_Non_Targeting_Human CCCGATGGACTATACCGAAC Human 560 1|sg_Non_Targeting_Human_GA_0127|Non_Targeting_ Non_Targeting_Human ACGTTCGAGTACGACCAGCTHuman 561 1|sg_Non_Targeting_ Human_GA_0128|Non_Targeting_Non_Targeting_Human CGCGACGACTCAACCTAGTC Human 562 1|sg_Non_Targeting_Human_GA_0129|Non_Targeting_ Non_Targeting_Human GGTCACCGATCGAGAGCTAGHuman 563 1|sg_Non_Targeting_ Non_Targeting_Human CTCAACCGACCGTATGGTCAHuman_GA_0130|Non_Targeting_ Human 564 1|sg_Non_Targeting_Non_Targeting_Human CGTATTCGACTCTCAACGCG Human_GA_0131|Non_Targeting_Human 565 1|sg_Non_Targeting_ Non_Targeting_Human CTAGCCGCCCAGATCGAGCCHuman_GA_0132|Non_Targeting_ Human 566 1|sg_Non_Targeting_Non_Targeting_Human GAATCGACCGACACTAATGT Human_GA_0133|Non_Targeting_Human 567 1|sg_Non_Targeting_ Non_Targeting_Human ACTTCAGTTCGGCGTAGTCAHuman_GA_0134|Non_Targeting_ Human 568 1|sg_Non_Targeting_Non_Targeting_Human GTGCGATGTCGCTTCAACGT Human_GA_0135|Non_Targeting_Human 569 1|sg_Non_Targeting_ Non_Targeting_Human CGCCTAATTTCCGGATCAATHuman_GA_0136|Non_Targeting_ Human 570 1|sg_Non_Targeting_Non_Targeting_Human CGTGGCCGGAACCGTCATAG Human_GA_0137|Non_Targeting_Human 571 1|sg_Non_Targeting_ Non_Targeting_Human ACCCTCCGAATCGTAACGGAHuman_GA_0138|Non_Targeting_ Human 572 1|sg_Non_Targeting_Non_Targeting_Human AAACGGTACGACAGCGTGTG Human_GA_0139|Non_Targeting_Human 573 1|sg_Non_Targeting_ Non_Targeting_Human ACATAGTCGACGGCTCGATTHuman_GA_0140|Non_Targeting_ Human 574 1|sg_Non_Targeting_Non_Targeting_Human GATGGCGCTTCAGTCGTCGG Human_GA_0141|Non_Targeting_Human 575 1|sg_Non_Targeting_ Non_Targeting_Human ATAATCCGGAAACGCTCGACHuman_GA_0142|Non_Targeting_ Human 576 1|sg_Non_Targeting_Non_Targeting_Human CGCCGGGCTGACAATTAACG Human_GA_0143|Non_Targeting_Human 577 1|sg_Non_Targeting_ Non_Targeting_Human CGTCGCCATATGCCGGTGGCHuman_GA_0144|Non_Targeting_ Human 578 1|sg_Non_Targeting_Non_Targeting_Human CGGGCCTATAACACCATCGA Human_GA_0145|Non_Targeting_Human 579 1|sg_Non_Targeting_ Non_Targeting_Human CGCCGTTCCGAGATACTTGAHuman_GA_0146|Non_Targeting_ Human 580 1|sg_Non_Targeting_Non_Targeting_Human CGGGACGTCGCGAAAATGTA Human_GA_0147|Non_Targeting_Human 581 1|sg_Non_Targeting_ Non_Targeting_Human TCGGCATACGGGACACACGCHuman_GA_0148|Non_Targeting_ Human 582 1|sg_Non_Targeting_Non_Targeting_Human AGCTCCATCGCCGCGATAAT Human_GA_0149|Non_Targeting_Human 583 1|sg_Non_Targeting_ Non_Targeting_Human ATCGTATCATCAGCTAGCGCHuman_GA_0150|Non_Targeting_ Human 584 1|sg_Non_Targeting_Non_Targeting_Human TCGATCGAGGTTGCATTCGG Human_GA_0151|Non_Targeting_Human 585 1|sg_Non_Targeting_ Non_Targeting_Human CTCGACAGTTCGTCCCGAGCHuman_GA_0152|Non_Targeting_ Human 586 1|sg_Non_Targeting_Non_Targeting_Human CGGTAGTATTAATCGCTGAC Human_GA_0153|Non_Targeting_Human 587 1|sg_Non_Targeting_ Non_Targeting_Human TGAACGCGTGTTTCCTTGCAHuman_GA_0154|Non_Targeting_ Human 588 1|sg_Non_Targeting_Non_Targeting_Human CGACGCTAGGTAACGTAGAG Human_GA_0155|Non_Targeting_Human 589 1|sg_Non_Targeting_ Non_Targeting_Human CATTGTTGAGCGGGCGCGCTHuman_GA_0156|Non_Targeting_ Human 590 1|sg_Non_Targeting_Non_Targeting_Human CCGCTATTGAAACCGCCCAC Human_GA_0157|Non_Targeting_Human 591 1|sg_Non_Targeting_ Non_Targeting_Human AGACACGTCACCGGTCAAAAHuman_GA_0158|Non_Targeting_ Human 592 1|sg_Non_Targeting_Non_Targeting_Human TTTACGATCTAGCGGCGTAG Human_GA_0159|Non_Targeting_Human 593 1|sg_Non_Targeting_ Non_Targeting_Human TTCGCACGATTGCACCTTGGHuman_GA_0160|Non_Targeting_ Human 594 1|sg_Non_Targeting_Non_Targeting_Human GGTTAGAGACTAGGCGCGCG Human_GA_0161|Non_Targeting_Human 595 1|sg_Non_Targeting_ Non_Targeting_Human CCTCCGTGCTAACGCGGACGHuman_GA_0162|Non_Targeting_ Human 596 1|sg_Non_Targeting_Non_Targeting_Human TTATCGCGTAGTGCTGACGT Human_GA_0163|Non_Targeting_Human 597 1|sg_Non_Targeting_ Non_Targeting_Human TACGCTTGCGTTTAGCGTCCHuman_GA_0164|Non_Targeting_ Human 598 1|sg_Non_Targeting_Non_Targeting_Human CGCGGCCCACGCGTCATCGC Human_GA_0165|Non_Targeting_Human 599 1|sg_Non_Targeting_ Non_Targeting_Human AGCTCGCCATGTCGGTTCTCHuman_GA_0166|Non_Targeting_ Human 600 1|sg_Non_Targeting_Non_Targeting_Human AACTAGCCCGAGCAGCTTCG Human_GA_0167|Non_Targeting_Human 601 1|sg_Non_Targeting_ Non_Targeting_Human CGCAAGGTGTCGGTAACCCTHuman_GA_0168|Non_Targeting_ Human 602 1|sg_Non_Targeting_Non_Targeting_Human CTTCGACGCCATCGTGCTCA Human_GA_0169|Non_Targeting_Human 603 1|sg_Non_Targeting_ Non_Targeting_Human TCCTGGATACCGCGTGGTTAHuman_GA_0170|Non_Targeting_ Human 604 1|sg_Non_Targeting_Non_Targeting_Human ATAGCCGCCGCTCATTACTT Human_GA_0171|Non_Targeting_Human 605 1|sg_Non_Targeting_ Non_Targeting_Human GTCGTCCGGGATTACAAAATHuman_GA_0172|Non_Targeting_ Human 606 1|sg_Non_Targeting_Non_Targeting_Human TAATGCTGCACACGCCGAAT Human_GA_0173|Non_Targeting_Human 607 1|sg_Non_Targeting_ Non_Targeting_Human TATCGCTTCCGATTAGTCCGHuman_GA_0174|Non_Targeting_ Human 608 1|sg_Non_Targeting_Non_Targeting_Human GTACCATACCGCGTACCCTT Human_GA_0175|Non_Targeting_Human 609 1|sg_Non_Targeting_ Non_Targeting_Human TAAGATCCGCGGGTGGCAACHuman_GA_0176|Non_Targeting_ Human 610 1|sg_Non_Targeting_Non_Targeting_Human GTAGACGTCGTGAGCTTCAC Human_GA_0177|Non_Targeting_Human 611 1|sg_Non_Targeting_ Non_Targeting_Human TCGCGGACATAGGGCTCTAAHuman_GA_0178|Non_Targeting_ Human 612 1|sg_Non_Targeting_Non_Targeting_Human AGCGCAGATAGCGCGTATCA Human_GA_0179|Non_Targeting_Human 613 1|sg_Non_Targeting_ Non_Targeting_Human GTTCGCTTCGTAACGAGGAAHuman_GA_0180|Non_Targeting_ Human 614 1|sg_Non_Targeting_Non_Targeting_Human GACCCCCGATAACTTTTGAC Human_GA_0181|Non_Targeting_Human 615 1|sg_Non_Targeting_ Non_Targeting_Human ACGTCCATACTGTCGGCTACHuman_GA_0182|Non_Targeting_ Human 616 1|sg_Non_Targeting_Non_Targeting_Human GTACCATTGCCGGCTCCCTA Human_GA_0183|Non_Targeting_Human 617 1|sg_Non_Targeting_ Non_Targeting_Human TGGTTCCGTAGGTCGGTATAHuman_GA_0184|Non_Targeting_ Human 618 1|sg_Non_Targeting_Non_Targeting_Human TCTGGCTTGACACGACCGTT Human_GA_0185|Non_Targeting_Human 619 1|sg_Non_Targeting_ Non_Targeting_Human CGCTAGGTCCGGTAAGTGCGHuman_GA_0186|Non_Targeting_ Human 620 1|sg_Non_Targeting_Non_Targeting_Human AGCACGTAATGTCCGTGGAT Human_GA_0187|Non_Targeting_Human 621 1|sg_Non_Targeting_ Non_Targeting_Human AAGGCGCGCGAATGTGGCAGHuman_GA_0188|Non_Targeting_ Human 622 1|sg_Non_Targeting_Non_Targeting_Human ACTGCGGAGCGCCCAATATC Human_GA_0189|Non_Targeting_Human 623 1|sg_Non_Targeting_ Non_Targeting_Human CGTCGAGTGCTCGAACTCCAHuman_GA_0190|Non_Targeting_ Human 624 1|sg_Non_Targeting_Non_Targeting_Human TCGCAGCGGCGTGGGATCGG Human_GA_0191|Non_Targeting_Human 625 1|sg_Non_Targeting_ Non_Targeting_Human ATCTGTCCTAATTCGGATCGHuman_GA_0192|Non_Targeting_ Human 626 1|sg_Non_Targeting_Non_Targeting_Human TGCGGCGTAATGCTTGAAAG Human_GA_0193|Non_Targeting_Human 627 1|sg_Non_Targeting_ Non_Targeting_Human CGAACTTAATCCCGTGGCAAHuman_GA_0194|Non_Targeting_ Human 628 1|sg_Non_Targeting_Non_Targeting_Human GCCGTGTTGCTGGATACGCC Human_GA_0195|Non_Targeting_Human 629 1|sg_Non_Targeting_ Non_Targeting_Human TACCCTCCGGATACGGACTGHuman_GA_0196|Non_Targeting_ Human 630 1|sg_Non_Targeting_Non_Targeting_Human CCGTTGGACTATGGCGGGTC Human_GA_0197|Non_Targeting_Human 631 1|sg_Non_Targeting_ Non_Targeting_Human GTACGGGGCGATCATCCACAHuman_GA_0198|Non_Targeting_ Human 632 1|sg_Non_Targeting_Non_Targeting_Human AAGAGTAGTAGACGCCCGGG Human_GA_0199|Non_Targeting_Human 633 1|sg_Non_Targeting_ Non_Targeting_Human AAGAGCGAATCGATTTCGTGHuman_GA_0200|Non_Targeting_ Human 634 3|sg_hCDC16_CC_1|CDC16 CDC16TCAACACCAGTGCCTGACGG 635 3|sg_hCDC16_CC_2|CDC16 CDC16AAAGTAGCTTCACTCTCTCG 636 3|sg_hCDC16_CC_3|CDC16 CDC16GAGCCAACCAATAGATGTCC 637 3|sg_hCDC16_CC_4|CDC16 CDC16GCGCCGCCATGAACCTAGAG 638 3|sg_hGTF2B_CC_1|GTF2B GTF2BACAAAGGTTGGAACAGAACC 639 3|sg_hGTF2B_CC_2|GTF2B GTF2BGGTGACCGGGTTATTGATGT 640 3|sg_hGTF2B_CC_3|GTF2B GTF2BTTAGTGGAGGACTACAGAGC 641 3|sg_hGTF2B_CC_4|GTF2B GTF2BACATATAGCCCGTAAAGCTG 642 3|sg_hHSPA5_CC_1|HSPA5 HSPA5CGTTGGCGATGATCTCCACG 643 3|sg_hHSPA5_CC_2|HSPA5 HSPA5TGGCCTTTTCTACCTCGCGC 644 3|sg_hHSPA5_CC_3|HSPA5 HSPA5AATGGAGATACTCATCTGGG 645 3|sg_hHSPA5_CC_4|HSPA5 HSPA5GAAGCCCGTCCAGAAAGTGT 646 3|sg_hHSPA9_CC_1|HSPA9 HSPA9CAATCTGAGGAACTCCACGA 647 3|sg_hHSPA9_CC_2|HSPA9 HSPA9AGGCTGCGGCGCCCACGAGA 648 3|sg_hHSPA9_CC_3|HSPA9 HSPA9ACTTTGACCAGGCCTTGCTA 649 3|sg_hHSPA9_CC_4|HSPA9 HSPA9ACCTTCCATAACTGCCACGC 650 3|sg_hPAFAH1B1_CC_ PAFAH1B1CGAGGCGTACATACCCAAGG 1|PAFAH1B1 651 3|sg_hPAFAH1B1_CC_ PAFAH1B1ATGGTACGGCCAAATCAAGA 2|PAFAH1B1 652 3|sg_hPAFAH1B1_CC_ PAFAH1B1TCTTGTAATCCCATACGCGT 3|PAFAH1B1 653 3|sg_hPAFAH1B1_CC_ PAFAH1B1ATTCACAGGACACAGAGAAT 4|PAFAH1B1 654 3|sg_hPCNA_CC_1|PCNA PCNACCAGGGCTCCATCCTCAAGA 655 3|sg_hPCNA_CC_2|PCNA PCNA TGAGCTGCACCAAAGAGACG656 3|sg_hPCNA_CC_3|PCNA PCNA ATGTCTGCAGATGTACCCCT 6573|sg_hPCNA_CC_4|PCNA PCNA CGAAGATAACGCGGATACCT 6583|sg_hPOLR2L_CC_1|POLR2L POLR2L GCTGCAGGCCGAGTACACCG 6593|sg_hPOLR2L_CC_2|POLR2L POLR2L ACAAGTGGGAGGCTTACCTG 6603|sg_hPOLR2L_CC_3|POLR2L POLR2L GCAGCGTACAGGGATGATCA 6613|sg_hPOLR2L_CC_4|POLR2L POLR2L GCAGTAGCGCTTCAGGCCCA 6623|sg_hRPL9_CC_1|RPL9 RPL9 CAAATGGTGGGGTAACAGAA 663 3|sg_hRPL9_CC_2|RPL9RPL9 GAAAGGAACTGGCTACCGTT 664 3|sg_hRPL9_CC_3|RPL9 RPL9AGGGCTTCCGTTACAAGATG 665 3|sg_hRPL9_CC_4|RPL9 RPL9 GAACAAGCAACACCTAAAAG666 3|sg_hSF3A3_CC_1|SF3A3 SF3A3 TGAGGAGAAGGAACGGCTCA 6673|sg_hSF3A3_CC_2|SF3A3 SF3A3 GGAAGAATGCAGAGTATAAG 6683|sg_hSF3A3_CC_3|SF3A3 SF3A3 GGAATTTGAGGAACTCCTGA 6693|sg_hSF3A3_CC_4|SF3A3 SF3A3 GCTCACCGGCCATCCAGGAA 6703|sg_hSF3B3_CC_1|SF3B3 SF3B3 ACTGGCCAGGAACGATGCGA 6713|sg_hSF3B3_CC_2|SF3B3 SF3B3 GCAGCTCCAAGATCTTCCCA 6723|sg_hSF3B3_CC_3|SF3B3 SF3B3 GAATGAGTACACAGAACGGA 6733|sg_hSF3B3_CC_4|SF3B3 SF3B3 GGAGCAGGACAAGGTCGGGG

Example 2—BRD9 Degrader Depletes BRD9 Protein

The following example demonstrates the depletion of the BRD9 protein insynovial sarcoma cells treated with a BRD9 degrader.

Procedure:

Cells were treated with DMSO or the BRD9 degrader, Compound 1 (alsoknown as dBRD9, see Remillard et al, Angew. Chem. Int. Ed. Engl.56(21):5738-5743 (2017); see structure of Compound 1 below), forindicated doses and timepoints.

Whole cell extracts were fractionated by SDS-PAGE and transferred to apolyvinylidene difluoride membrane using a transfer apparatus accordingto the manufacturer's protocols (Bio-Rad). After incubation with 5%nonfat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for60 minutes, the membrane was incubated with antibodies against BRD9(1:1,000, Bethyl laboratory A³⁰³-781A), GAPDH (1:5,000, Cell SignalingTechnology), and/or MBP (1:1,000, BioRad) overnight at 4° C. Membraneswere washed three times for 10 min and incubated with anti-mouse oranti-rabbit antibodies conjugated with either horseradish peroxidase(HRP, FIGS. 2-3 ) or IRDye (FIG. 4 , 1:20,000, LI-COR) for at least 1 h.Blots were washed with TBST three times and developed with either theECL system according to the manufacturer's protocols (FIGS. 2-3 ) orscanned on an Odyssey CLx Imaging system (FIG. 4 ).

Results:

Treatment of SYO1 synovial sarcoma cells with the BRD9 degrader Compound1 results in dose dependent (FIG. 2 ) and time dependent (FIG. 3 )depletion of BRD9 in the cells. Further, as shown in FIG. 4 , thedepletion of BRD9 by Compound 1 is replicated in a non-synovial sarcomacell line (293T) and may be sustained for at least 5 days.

Example 3—Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitorsand BRD9 Degraders

The following example demonstrates that BRD9 degraders and inhibitorsselectively inhibit growth of synovial sarcoma cells.

Procedures:

Cells were treated with DMSO or the BRD9 degrader, Compound 1, atindicated concentrations, and proliferation was monitored from day 7 today 14 by measuring confluency over time using an IncuCyte live cellanalysis system (FIG. 5 ). Growth medium and compounds were refreshedevery 3-4 days.

Cells were seeded into 12-well plates and treated with DMSO, 1 μM BRD9inhibitor, Compound 2 (also known as BI-7273, see Martin et al, J MedChem. 59(10):4462-4475 (2016); see structure of Compound 2 below), or 1μM BRD9 degrader, Compound 1.

The number of cells was optimized for each cell line. Growth medium andcompounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T andHS-SY-II cells were fixed and stained at day 11. ASKA cells were fixedand stained at day 23. Staining was done by incubation with crystalviolet solution (0.5 g Crystal Violet, 27 ml 37% Formaldehyde, 100 mL10×PBS, 10 mL Methanol, 863 dH2O to 1 L) for 30 min followed by 3×washes with water and drying the plates for at least 24 h at roomtemperature. Subsequently plates were scanned on an Odyssey CLx Imagingsystem (FIG. 6 ).

Cells were seeded into 96-well ultra low cluster plate (Costar, #7007)in 200 μL complete media and treated at day 2 with DMSO, Staurosporin,or BRD9 degarder, Compound 1, at indicated doses (FIG. 7 ). Media andcompounds were changed every 5 d and cell colonies were imaged at day14.

Results:

As shown in FIGS. 5, 6, and 7 , treatment of synovial sarcoma cell lines(SYO1, Yamato, HS-SY-II, and ASKA) with a BRD9 inhibitor, Compound 2, ora BRD9 degrader, Compound 1, results in inhibition of the growth of thecells, but does not result in inhibition of the growth of non-synovialcontrol cancer cell lines (293T, A549, G401).

Example 4—Selective Inhibition of Growth of Synovial Cell Lines by BRD9Degraders and BRD9 Binders

The following example demonstrates that BRD9 degraders and bindersselectively inhibit growth of synovial sarcoma cells.

Procedure:

Cells were seeded into 6-well or 12-well plates and were treated dailywith a BRD9 degrader (Compound 1), a bromo-domain BRD9 binder (Compound2), E3 ligase binder (lenalidomide), DMSO, or staurosporin (positivecontrol for cell killing), at indicated concentrations. The number ofcells was optimized for each cell line. Growth media was refreshed every5 days. By day 14, medium was removed, cells were washed with PBS, andstained using 500 μL of 0.005% (w/v) crystal violet solution in 25%(v/v) methanol for at least 1 hour at room temperature. Subsequentlyplates were scanned on an Odyssey CLx Imaging system.

Results:

As shown in FIGS. 8 and 9 , treatment of synovial sarcoma cell lines(SYO1, HS-SY-II, and ASKA) with Compound 1 or Compound 2 resulted ininhibition of the growth of the cells, but did not result in inhibitionof the growth of non-synovial control cancer cell lines (RD, HCT116, andCalu6). Overall, Compound 1 showed most significant growth inhibition inall synovial cell lines.

Example 5—Inhibition of Cell Growth in Synovial Sarcoma Cells

The following example shows that BRD9 degraders inhibit cell growth andinduce apoptosis in synovial sarcoma cells.

Procedure:

SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9 degrader(Compound 1) at 200 nM or 1 μM, or an E3 ligase binder (lenalidomide) at200 nM. Compounds were refreshed every 5 days. Cell cycle analysis wasperformed using the Click-iT™ Plus EdU Flow Cytometry Assay(Invitrogen). The apoptosis assay was performed using the Annexin V-FITCApoptosis Detection Kit (Sigma A9210). Assays were performed accordingto the manufacturer's protocol.

Results:

As shown in FIGS. 10-13 , treatment with Compound 1 for 8 or 13 daysresulted in reduced numbers of cells in the S-phase of the cell cycle ascompared to DMSO and lenalidomide. Treatment with Compound 1 for 8 daysalso resulted in increased numbers of early- and late-apoptotic cells ascompared to DMSO controls.

Example 6—Composition for SS18-SSX1-BAF

The following example shows the identification of BRD9 as a component ofSS18-SSX containing BAF complexes.

Procedure:

A stable 293T cell line expressing HA-SS18SSX1 was generated usinglentiviral integration. SS18-SSX1 containing BAF complexes were subjectto affinity purification and subsequent mass spectrometry analysisrevealed SS18-SSX1 interacting proteins.

Results:

As shown in FIG. 14 , BAF complexes including the SS18-SSX fusionprotein also included BRD9. More than 5 unique peptides were identifiedfor ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides),SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides),SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1Isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides).

Example 7—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-6-(methylamino)-1,2-dihydro-2,7-naphthyridin-1-one(Compound B1)

To a stirred mixture of6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(100 mg, 0.26 mmol, 1.0 equiv) and methanamine hydrochloride (174.08 mg,2.58 mmol, 10.0 equiv) in DMSO (3 mL) was added K₂CO₃ (890.82 mg, 6.45mmol, 25.0 equiv) at room temperature. The resulting mixture was stirredfor 16 hours at 130° C., and then it was allowed to cool down to roomtemperature. The solid was filtered off, the crude solution was purifiedby Prep-HPLC (conditions: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 40mL/minute; Gradient: 18% B to 18% B in 2 minutes; 254/220 nm; Rt: 7.43minutes) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-6-(methylamino)-1,2-dihydro-2,7-naphthyridin-1-one(27 mg, 26%). ¹H NMR (400 MHz, Methanol-d4) δ 9.08 (s, 1H), 7.40 (s,1H), 6.74 (s, 2H), 6.44 (s, 1H), 3.88 (s, 6H), 3.69 (s, 2H), 3.58 (s,3H), 2.88 (s, 3H), 2.33 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=383.20.

Example 8—Preparation of6-(dimethylamino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(Compound B2)

To a stirred mixture of6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(77.6 mg, 0.20 mmol, 1.0 equiv) and dimethylamine hydrochloride (163.14mg, 2.0 mmol, 10.0 equiv) in DMF (6 mL) was added TEA (404.91 mg, 4.0mmol, 20.0 equiv) at room temperature. The resulting mixture was stirredfor 16 hours at 130° C. and then it was allowed to cool down to roomtemperature. The solid was filtered off, the filtrate was purified byPrep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column,X Bridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water(0.05% NH₃H₂O) and ACN (10% Phase B up to 70% in 8 minutes); To afford23 mg (27%) of6-(dimethylamino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-oneas a brown solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.43 (s,1H), 6.77 (s, 2H), 6.52 (s, 1H), 3.89 (s, 6H), 3.70 (s, 2H), 3.59 (s,3H), 3.12 (s, 6H), 2.34 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=397.40.

Example 9—Preparation of4-[4-[(Dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-7-(methylamino)-1,2-dihydro-2,6-naphthyridin-1-one(Compound B3)

To a solution of7-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,6-naphthyridin-1-one(50 mg, 0.13 mmol, 1.0 equiv) and methanamine hydrochloride (87.0 mg,1.29 mmol, 10.0 equiv) in solvent DMSO (2 mL) was added K₂CO₃ (445.4 mg,3.22 mmol, 25.0 equiv). The resulting solution was stirred at 130° C.for overnight. After cooling, the solid was filtered off, the crudesolution was purified by Prep-HPLC (conditions: XBridge Shield RP18 OBDColumn, 5 μm, 19*150 mm; Mobile Phase A: Water (0.05% NH₃H₂O), MobilePhase B: ACN; Flow rate: 25 mL/minute; Gradient: 30% B to 80% B in 8minutes; 220 nm nm; Rt: 7.8 minutes) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-7-(methylamino)-1,2-dihydro-2,6-naphthyridin-1-one(15.5 mg, 31%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.53(d, J=0.9 Hz, 1H), 7.24 (d, J=0.9 Hz, 1H), 7.09 (s, 1H), 6.76 (s, 2H),3.88 (s, 6H), 3.67 (d, J=11.1 Hz, 5H), 2.97 (s, 3H), 2.31 (s, 6H). LCMS:(ES, m/z): [M+H]⁺=383.30.

Example 10—Preparation of6-amino-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(Compound B4) and7-amino-4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(Compound B5)

Step 1: Preparation of 4-bromo-6-chloro-N-methylpyridine-3-carboxamide(i10-2)

To a solution of 4-bromo-6-chloropyridine-3-carboxylic acid (2.0 g, 8.46mmol, 1.0 equiv), methanamine hydrochloride (0.63 g, 9.30 mmol, 1.1equiv) and DIEA (3.28 g, 25.38 mmol, 3.0 equiv) in DCM (20 mL) was addedHATU (4.82 g, 12.69 mmol, 1.5 equiv) at room temperature. The resultingmixture was stirred for another 1 hour. Then the reaction was washedwith water (20 m×2), and the organic layer was concentrated under vacuumto give a yellow syrup. The product was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=249.

Step 2: Preparation of6-chloro-4-[(E)-2-ethoxyethenyl]-N-methylpyridine-3-carboxamide (i10-3)

To a solution of 4-bromo-6-chloro-N-methylpyridine-3-carboxamide (1.0 g,4.0 mmol, 1 equiv) and2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.95 g,4.81 mmol, 1.2 equiv) in dioxane (10 mL) and H₂O (2 mL) was added Cs₂CO₃(3.92 g, 12.03 mmol, 3.0 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (0.35 g, 0.48mmol, 0.12 equiv). The mixture was stirred for 2 hours at 90° C. undernitrogen atmosphere, and the reaction mixture was dilute with water andextracted with ethyl acetate, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford6-chloro-4-[(E)-2-ethoxyethenyl]-N-methylpyridine-3-carboxamide (680 mg,57%) as an off-white solid. LCMS (ESI) m/z: [M+H]⁺=241.

Step 3: 6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (i10-4)

Into a 20 mL pressure tube was added6-chloro-4-[(E)-2-ethoxyethenyl]-N-methylpyridine-3-carboxamide (680 mg,2.83 mmol, 1.0 equiv) and TFA (5 mL, 67.32 mmol, 23.83 equiv) at roomtemperature, the reaction was stirred over night at 80° C. The resultingmixture was concentrated under vacuum to afford6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (580 mg, crude) asa dark yellow solid. The product was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=195.

Step 4: Preparation of4-bromo-6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (i10-5)

To a stirred mixture of6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (580 mg, 2.98 mmol,1.0 equiv) in DMF (10 mL) was added NBS (583.46 mg, 3.28 mmol, 1.1equiv), and the resulting mixture was stirred for 2 hours at roomtemperature. The reaction mixture was diluted with DCM (50 mL) andwashed with water (3×50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under vacuum. The crude product was purified by flashsilica chromatography, eluted with 0 to 80% EtOAc in petroleum ether.Pure fractions were evaporated to dryness to afford4-bromo-6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (899 mg,88%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=273.

Step 5: Preparation of6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(i10-6)

To a solution of4-bromo-6-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (843 mg,3.08 mmol, 1.0 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (736.88 mg,3.08 mmol, 1.0 equiv) in dioxane (40 mL) and H₂O (4 mL) was added Cs₂CO₃(3.01 g, 9.25 mmol, 3.0 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (302.04 mg, 0.37mmol, 0.12 equiv). After stirring for 2 hours at 90° C. under a nitrogenatmosphere, the reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄ and thenconcentrated under reduced pressure. The crude product was purified byflash silica chromatography, eluted with 0 to 80% EtOAc in petroleumether. Pure fractions were evaporated to dryness to afford6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(670 mg, 51%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=388.

Step 6: Preparation of6-amino-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(Compound B4)

To a stirred mixture of6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(232 mg, 060 mmol, 1.0 equiv) and NH₄Cl (479.94 mg, 8.97 mmol, 15.0equiv) in DMSO (10 mL) was added K₂CO₃ (2.07 g, 14.95 mmol, 25.0 equiv).The resulting mixture was stirred overnight at 130° C. After completionof the reaction, the reaction mixture was diluted with water andextracted with ethyl acetate, dried over Na₂SO₄, and then concentratedunder reduced pressure. The crude product was purified by Prep-HPLC(conditions: X Select CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobilephase, Water (0.1% FA) and ACN (hold 7% Phase B in 7 minutes); Detector,UV) to afford 3.4 mg (1.54%) of6-amino-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphth-yridin-1-oneas an off-white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.04 (s, 1H),7.44 (s, 1H), 6.84 (s, 2H), 6.54 (s, 1H), 4.34 (s, 2H), 3.97 (s, 6H),3.59 (s, 3H), 2.85 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=369.25.

Preparation of7-amino-4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(Compound B5)

Compound B5 was prepared in a similar manner as described above forcompound B4. ¹H NMR (300 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.65 (d,J=2.2 Hz, 1H), 7.23 (s, 1H), 6.89 (s, 2H), 4.42 (s, 2H), 3.98 (s, 6H),3.64 (s, 3H), 2.92 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=369.25.

Example 11—Preparation of2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]-N,N-dimethylacetamideformic acid (Compound B6 Formic Acid)

To a stirred mixture of[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]aceticacid (60.0 mg, 0.141 mmol, 1.00 equiv) and dimethylamine hydrochloride(17.2 mg, 0.211 mmol, 1.50 equiv) in DMF (2.00 mL) was added DIEA (54.6mg, 0.422 mmol, 3.00 equiv). The mixture was stirred at room temperaturefor 5 minutes, and then PyBOP (146.43 mg, 0.281 mmol, 2.00 equiv) wasadded. After stirring at room temperature for 2 hours, the reactionmixture was purified by Prep-HPLC (conditions: Sun Fire C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN(10% Phase B up to 31% in 11 minutes). This resulted in2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]-N,N-dimethylacetamide; formic acid (10.9 mg, 17.7%) as a dark yellow solid. ¹H NMR(300 MHz, Methanol-d4) δ 8.51 (br s, 0.5H, FA), 8.50 (s, 1H), 7.37 (s,1H), 7.16 (s, 1H), 6.92 (s, 2H), 4.92 (s, 2H), 4.37 (s, 2H), 3.95 (s,6H), 3.65 (s, 3H), 3.36 (s, 6H), 3.05 (d, J=5.5 Hz, 6H). LCMS (ESI) m/z:[M+H]⁺=454.20.

Example 12—Preparation of1-([4-[6-(Dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]pentyl)azetidine-3-carboxamide(Compound D1)

Step 1: Preparation of4-[6-(Dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(i12-2)

To a solution of4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one (400.00 mg,1.42 mmol, 1.00 eq.) in dioxane (10.00 mL) and H₂O (1.00 mL) was added2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(500 mg, 1.70 mmol, 1.2 eq.), Pd(dppf)Cl₂ (100.0 mg, 0.14 mmol, 0.1eq.), and Cs₂CO₃ (1.39 g, 4.14 mmol, 3 eq.). The resulting solution wasstirred at 90° C. for 1 hour under a nitrogen atmosphere. The crude wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(416.8 mg, 119.03%) as a light yellow solid. LCMS (ESI) m/z:[M+H]+=367.4.

Step 2: Preparation of Methyl1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylate(i12-3)

To a solution of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(331.00 mg, 0.901 mmol, 1.00 eq.) in MeOH (10.00 mL) was added methylazetidine-3-carboxylate hydrochloride (163.88 mg, 1.081 mmol, 1.2 eq.)and NaBH₃CN (169.85 mg, 2.703 mmol, 3 eq.). The resulting solution wasstirred at room temperature for 1 hour. The crude mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to affordmethyl1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylate(279 mg, 66.38%) as a light yellow solid. LCMS (ESI) m/z: [M+H]⁺=466.5.

Step 3: Preparation of1-([4-[6-(Dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylicacid (i12-4)

To the solution of methyl1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylate(140.00 mg, 0.300 mmol, 1.00 eq.) in MeOH (3.00 mL) and H₂O (3.00 mL)was added LiOH (71.87 mg, 3.001 mmol, 10.00 eq.). The resulting solutionwas stirred at room temperature for 3 hours. The crude mixture wasconcentrated under reduced pressure. The residue was purified by reverseflash chromatography (conditions: column, C18 silica gel; mobile phase,HCl in water, 10% to 70% gradient in 35 minutes; detector, UV 254 nm).This resulted in1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylicacid (120 mg, 88.37%) as a white solid. LCMS (ESI) m/z: [M+H]+=452.5.

Step 4: Preparation of1-([4-[6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]pentyl)azetidine-3-carboxamide(Compound D1 Formic Acid)

To a solution of1-([4-[6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidine-3-carboxylicacid (50.00 mg, 0.110 mmol, 1.00 eq.) and4-[(5-aminopentyl)oxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(39.71 mg, 0.110 mmol, 1.00 eq.) in DMF (1.50 mL) was added DIEA (42.84mg, 0.331 mmol, 3.00 eq.) and PyBOP (86.25 mg, 0.166 mmol, 1.50 eq.).The resulting solution was stirred at room temperature for 1 hour. Thecrude product (50 mg) was purified by Prep-HPLC (conditions: SunFire C18OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 11% B to27% B in 18 minutes; 254 nm; R_(t): 16.87 minutes) to afford1-([4-[6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]pentyl)azetidine-3-carboxamideformate (13.5 mg) as a light yellow solid. ¹H NMR (300 MHz,Acetonitrile-d3) δ 9.12 (s, 1H), 8.17 (s, 0.3H, FA), 7.76 (dd, J=8.5,7.3 Hz, 1H), 7.53-7.28 (m, 3H), 6.79 (s, 2H), 6.65 (s, 1H), 6.53 (s,1H), 4.99 (dd, J=12.1, 5.4 Hz, 1H), 4.26 (s, 2H), 4.23-4.15 (m, 2H),4.15-4.03 (m, 2H), 4.04-3.92 (m, 2H), 3.87 (s, 6H), 3.52 (s, 3H), 3.42(t, J=8.1 Hz, 1H), 3.34-3.12 (m, 3H), 3.10 (s, 6H), 2.86-2.62 (m, 3H),2.21-2.07 (m, 1H), 1.88-1.76 (m, 2H), 1.63-1.50 (m, 4H). LCMS (ESI) m/z:[M+H]+=452.45.

Example 13—Preparation of4-(((((S)-1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D2)

Step 1: Preparation of tert-butyl(S)-2((2,2,2-trifluoroacetamido)methyl)azetidine-1-carboxylate (i13-2)

To a solution of tert-butyl (2S)-2-(aminomethyl)azetidine-1-carboxylate(900.00 mg, 4.832 mmol, 1.00 equiv) and trifluoroacetic anhydride (1.522g, 7.248 mmol, 1.5 equiv) in THF (9.00 mL) was added TEA (977.92 mg,9.664 mmol, 2 equiv). The resulting solution was stirred at 25° C. for12 hours. The resulting solution was diluted with of EtOAc. Theresulting mixture was washed with water (3×50 mL), then dried overanhydrous sodium sulfate, filtered, and concentrated to give crudeproduct that was applied onto a silica gel column with ethyl EA/PE(15:85) to afford tert-butyl (2S)-2-[(2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (1.27 g, 93.11%) as a yellow oil. LCMS(ESI) m/z: [M+H]+=283.

Step 2: Preparation of tert-butyl(S)-2-((2,2,2-trifluoro-N-methylacetamido)methyl)azetidine-1-carboxylate(i13-3)

To a solution of tert-butyl(2S)-2-[(2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (1.27g, 4.499 mmol, 1.00 equiv) and dimethyl sulfate (681.00 mg, 5.399 mmol,1.2 equiv) in acetone (15.00 mL) was added K₂CO₃ (621.83 mg, 4.499 mmol,1 equiv). The resulting solution was stirred at 25° C. for 12 hours. Theresulting mixture was filtered, and the filtrate was evaporated todryness to afford tert-butyl(2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate(1.64 g, crude) as a yellow oil that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=297.

Step 3: Preparation of(S)—N-(azetidin-2-ylmethyl)-2,2,2-trifluoro-N-methylacetamide (i13-4)

A solution of tert-butyl(2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate(1.64 g, 5.535 mmol, 1.00 equiv) and TFA (3.50 mL, 47.121 mmol, 8.51equiv) in DCM (16.00 mL) was stirred for 1 hour at 25° C. The mixturewas concentrated to giveN-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (2.08 g,crude) as a brown oil that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=197.

Step 4: Preparation of(S)—N-((1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)azetidin-2-yl)methyl)-2,2,2-trifluoro-N-methylacetamide(i13-5)

To a solution of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(620.00 mg, 1.688 mmol, 1.00 equiv) andN-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (496.57mg, 2.531 mmol, 1.50 equiv) in DMF (5.00 mL, 64.609 mmol, 38.29 equiv)was added NaBH(OAc)₃ (715.31 mg, 3.375 mmol, 2 equiv). The resultingsolution was stirred at 25° C. for 1 hour. The mixture was concentratedto give crude product that was purified by chromatography on silica geleluted with MeOH]/DCM (4.2:95.8) to giveN-[[(2S)-1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide(436 mg, 47.18%) as a dark yellow solid. LCMS (ESI) m/z: [M+H]+=548.

Step 5: Preparation of(S)-4-(3,5-dimethoxy-4-((2-((methylamino)methyl)azetidin-1-yl)methyl)phenyl)-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1(2H)-one(6)

A solution ofN-[[(2S)-1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide(400.00 mg, 0.730 mmol, 1.00 equiv) and NH₃.H₂O (2.00 mL, 51.361 mmol,70.31 equiv) in DMF (4.00 mL, 12.922 mmol, 196.55 equiv) was stirred at25° C. for 12 hours. The resulting solution was concentrated to givecrude product4-(3,5-dimethoxy-4-[[(2S)-2-[(methylamino)methyl]azetidin-1-yl]methyl]phenyl)-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one(458 mg) as a brown solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=452.

Step 6: Preparation of4-(S)-1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D2)

4-(3,5-dimethoxy-4-[[(2R)-2-[(methylamino)methyl]azetidin-1-yl]methyl]phenyl)-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one(100.00 mg, 0.221 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-carbaldehyde (63.39 mg,0.221 mmol, 1.00 equiv) were dissolved in MeOH (2.00 mL). Then NaBH₃CN(69.58 mg, 1.107 mmol, 5 equiv) was added to the mixture, and theresulting solution was stirred at 25° C. for 1 hour. Without anyadditional work-up, the mixture was purified by prep-HPLC (conditions:SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A:Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:9% B to 19% B in 15 minutes; 254 nm; Rt: 17.67 minutes) to give4-(((((S)-1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoli-ne-1,3-dione(20.4 mg, 12.76%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ9.05 (s, 1H), 8.00-7.74 (m, 3H), 7.51 (d, J=6.9 Hz, 1H), 6.88 (d, J=5.4Hz, 2H), 6.60 (d, J=4.5 Hz, 1H), 5.26-5.05 (m, 1H), 4.64 (dd, J=12.8,10.2 Hz, 1H), 4.53 (dd, J=12.8, 5.7 Hz, 1H), 4.27-4.08 (m, 4H), 3.93 (d,J=10.8 Hz, 6H), 3.59 (d, J=2.1 Hz, 3H), 3.16 (s, 6H), 3.10 (s, 2H),2.95-2.80 (m, 1H), 2.80-2.58 (m, 3H), 2.32 (dd, J=15.9, 2.4 Hz, 4H),2.19-2.08 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=722.20.

Example 14—Preparation of4-([[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl](methyl)amino]methyl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D3 Formic Acid)

Step 1: Preparation of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(i14-2)

To a solution of4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one (1.80 g, 6.380mmol, 1.00 equiv) and 4-formyl-3,5-dimethoxyphenylboronic acid (1.34 g,6.380 mmol, 1.00 equiv) in 1,4-dioxane and water was added CS₂CO₃ (4.16g, 12.760 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (0.47 g, 0.638 mmol, 0.10equiv). After stirring for 2 hours at 80° C. under a nitrogenatmosphere, the resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (1:1) to afford4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(1.5 g, 57.59%) as a grey solid. LCMS (ESI) m/z: [M+H]+=368.

Step 2: Preparation oftert-butyl-N-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]-N-methylcarbamate(i14-3)

To a stirred mixture of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(100.00 mg, 0.272 mmol, 1.00 equiv) and tert-butylN-(azetidin-3-yl)-N-methylcarbamate hydrochloride (90.93 mg, 0.408 mmol,1.50 equiv) in MeOH was added NaBH₃CN (34.21 mg, 0.544 mmol, 2.00 equiv)in portions. The resulting mixture was stirred for 2 hours at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluted withDCM/MeOH (20:1) to affordtert-butyl-N-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]-N-methylcarbamate(103 mg, 65.46%) as an off-white solid. LCMS (ESI) m/z: [M+H]⁺=538.

Step 3:4-(3,5-dimethoxy-4-((3-(methylamino)azetidin-1-yl)methyl)phenyl)-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1(2H)-one(i14-44)

To a stirred solution oftert-butyl-N-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]-N-methylcarbamate(100.00 mg, 0.186 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.20mL, 2.693 mmol, 14.48 equiv). The resulting mixture was stirred for 2hours at room temperature and concentrated under reduced pressure. Theresidue was used in the next step directly without further purification.LCMS (ESI) m/z: [M+H]⁺=438.

Step 4: Preparation of4-([[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl](methyl)amino]methyl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D3 Formic Acid)

To a stirred mixture of4-(3,5-dimethoxy-4-[[3-(methylamino)azetidin-1-yl]methyl]phenyl)-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one(50.00 mg, 0.114 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-carbaldehyde (65.42 mg,0.229 mmol, 2.00 equiv) in MeOH was added NaBH₃CN (14.36 mg, 0.229 mmol,2.00 equiv) in portions. The resulting mixture was stirred for 2 hoursat room temperature. The mixture was purified by Prep-HPLC (conditions:XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water(0.1% FA) and ACN (16% PhaseB up to 26% in 8 minutes); Detector, UV).This resulted in4-([[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl](methyl)amino]methyl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (2.8 mg, 3.17%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.16 (d, J=0.7 Hz, 1H), 8.56 (br s, 1H, FA), 7.90-7.79(m, 3H), 7.43 (s, 1H), 6.85 (s, 2H), 6.47 (s, 1H), 5.14 (dd, J=12.3, 5.4Hz, 1H), 4.37 (s, 2H), 4.06 (s, 3H), 3.98-3.85 (m, 9H), 3.59 (s, 3H),3.55-3.45 (m 1H), 3.11 (s, 6H), 2.89-2.80 (m, 1H), 2.77-2.66 (m, 2H),2.16 (s, 3H), 2.14-2.07 (m, 1H). LCMS (ESI) m/z: [M+H]+=708.30.

Example 15—Preparation of(2S)-1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-2-carboxamideformic acid (Compound D4 Formic Acid)

Compound D4 was prepared in a similar manner to Example 12.(2S)-1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-2-carboxamideformic acid (9.1 mg, 17.56%) was obtained as a light yellow solid. ¹HNMR (400 MHz, Methanol-d4) δ 9.18-9.11 (m, 1H), 8.54 (s, 0.2H, FA),7.93-7.52 (m, 2H), 7.46-7.27 (m, 2H), 6.85 (s, 2H), 6.54-6.30 (m, 1H),5.34-4.94 (m, 4H), 4.48-4.31 (m, 2H), 4.03-3.79 (m, 8H), 3.91 (s, 3H),3.14-2.93 (m, 9H), 2.90-2.67 (m, 4H), 2.60-2.38 (m, 1H), 2.23-2.09 (m,1H). LCMS (ESI) m/z: [M+H]⁺=736.45.

Example 16—Preparation of1[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamide formic acid (Compound D5 Formic Acid)

Step 1: Preparation oftert-butyl-N-[8-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]octyl]carbamate(i16-1)

Using a similar procedure as described in Example 7 and substitutingwith tert-butyl N-(8-aminooctyl)carbamate (945 mg, 3.867 mmol) affordedtert-butyl-N-[8-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]octyl]carbamate(140 mg, 82%) as a yellow syrup. LCMS (ESI) m/z: [M+H]⁺=596.

Step 2: Preparation of6-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(i16-2)

To a stirred mixture oftert-butyl-N-[8-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]octyl]carbamate(140 mg, 0.235 mmol, 1.00 equiv) in dichloromethane (2.0 mL) was addedtrifluoroacetic acid (0.50 mL, 6.732 mmol, 28.65 equiv). The resultingmixture was stirred for 2 hours at room temperature. The resultingmixture was concentrated under reduced pressure, and the residue waspurified by reverse flash chromatography (conditions: column, C18 silicagel; mobile phase, acetonitrile in water (0.1% formic acid), 1% to 20%gradient in 20 minutes; detector, UV 254 nm) to give6-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(100 mg, 80%) as a yellow syrup. LCMS (ESI) m/z: [M+H]⁺=596.

Step 3: Preparation ofN-[8-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamideformic acid (Compound D5 Formic Acid)

Using a similar procedure as described in Example 11 and substitutingwith of6-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(50.0 mg, 0.101 mmol, 1.00 equiv) and[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(30.2 mg, 0.091 mmol, 0.90 equiv) affordedN-[8-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamideformic acid (6.2 mg, 7%) as a white solid. ¹H NMR (400 MHz, Methanol-d4)δ 9.05 (d, J=0.7 Hz, 1H), 8.57 (br s, 1H, FA), 7.81 (dd, J=8.4, 7.3 Hz,1H), 7.53 (d, J=7.3 Hz, 1H), 7.46-7.38 (m, 2H), 6.83 (s, 2H), 6.40 (s,1H), 5.13 (dd, J=12.6, 5.5 Hz, 1H), 4.76 (s, 2H), 4.60 (s, 3H), 4.23 (s,2H), 3.95 (s, 6H), 3.57 (s, 3H), 3.34-3.23 (m, 2H), 2.93-2.81 (m, 2H),2.80-2.67 (m, 6H), 2.19-2.10 (m, 1H), 1.62-1.54 (m, 4H), 1.37-1.33 (m,8H). LCMS (ESI) m/z: [M+H]⁺=810.45.

Example 17—Preparation of4-((5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D6 Formic Acid)

Step 1: Preparation of4-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-6-((5-hydroxypentyl)amino)-2-methyl-2,7-naphthyridin-1(2H)-one(i17-2)

Using a similar procedure as described in Example 7 and substitutingwith6-chloro-4-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(150.0 mg, 0.387 mmol, 1.00 equiv) and 5-aminopentanol (39.8 mg, 0.387mmol, 1.00 equiv) afforded4-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-6-((5-hydroxypentyl)amino)-2-methyl-2,7-naphthyridin-1(2H)-one(90 mg, 51.4%) as a brown solid. LCMS (ESI) m/z: [M+H]⁺=455.

Step 2: Preparation of5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentylmethanesulfonate (i17-3)

To a solution of4-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-6-((5-hydroxypentyl)amino)-2-methyl-2,7-naphthyridin-1(2H)-one (90 mg, 0.198 mmol, 1.00equiv) and triethylamine (100.2 mg, 0.990 mmol, 5.00 equiv) indichloromethane (2.00 mL) was added methanesulfonyl chloride (45.4 mg,0.396 mmol, 2.00 equiv) slowly at 0° C. The reaction mixture was stirredfor 30 minutes at 0° C. and then warmed to room temperature slowly. Thereaction was quenched with saturated sodium bicarbonate solution (50 mL)and extracted with dichloromethane (50 mL×3). The organic layers werecombined and washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentylmethanesulfonate (80.0 mg, 68.3%) as a brown solid. LCMS (ESI) m/z:[M+H]⁺=533.

Step 3: Preparation of4-((5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (Compound D6Formic Acid)

To a mixture of5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentyl methanesulfonate (80.0 mg,0.150 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (41.2 mg,0.150 mmol, 1.00 equiv) in DMF (2.00 mL) was added K₂CO₃ (41.5 mg, 0.300mmol, 2.00 equiv). The resulting mixture was stirred for 4 hours at 60°C. The resulting mixture was filtered, and the filtrate was purified byPrep-HPLC (column: SunFire C₁₈ OBD Prep Column, 100 Å, 5 μm, 19 mm×250mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 11% B to 26% B in 10 minutes; 254 nm; Rt: 8.78minutes) to afford4-((5-((5-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)amino)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;formate (15.3 mg, 11.6%) as a light yellow solid. LCMS (ESI) m/z:[M+H]⁺=711.65. ¹H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 1H), 8.56 (br s,0.6H, FA), 7.77 (dd, J=8.5, 7.3 Hz, 1H), 7.43 (dd, J=11.8, 7.8 Hz, 2H),7.28 (s, 1H), 7.16 (s, 1H), 7.01 (s, 1H), 5.98 (s, 1H), 5.09 (dd,J=12.8, 5.4 Hz, 1H), 4.22 (t, J=6.2 Hz, 2H), 4.03 (s, 2H), 3.88 (s, 3H),3.75 (s, 3H), 3.56 (s, 3H), 3.28 (t, J=6.6 Hz, 2H), 2.93-2.82 (m, 1H),2.80-2.70 (m, 2H), 2.65 (s, 6H), 2.15-2.07 (m, 1H), 1.92-1.81 (m, 2H),1.73-1.64 (m, 2H), 1.64-1.55 (m, 2H).

Example 18—Preparation of1-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)azetidine-3-carboxamideformic acid (Compound D7 Formic Acid)

Compound 7 was prepared in a similar manner to Example 10 and Example12.1-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)azetidine-3-carboxamideformic acid (30 mg, 30.6%) was obtained as a yellow solid. ¹H NMR (300MHz, Methanol-d4) δ 8.56 (br s, 0.7H, FA), 8.51 (d, J=0.9 Hz, 1H), 7.77(dd, J=8.4, 7.4 Hz, 1H), 7.44 (dd, J=7.9, 2.5 Hz, 2H), 7.23 (d, J=0.9Hz, 1H), 7.10 (s, 1H), 6.81 (s, 2H), 5.10 (dd, J=12.4, 5.5 Hz, 1H),4.30-4.21 (m, 3H), 4.02 (d, J=8.1 Hz, 3H), 3.92 (s, 6H), 3.64 (s, 3H),3.47 (t, J=8.2 Hz, 1H), 3.29-3.13 (m, 3H), 2.97 (s, 3H), 2.90-2.76 (m,2H), 2.75-2.63 (m, 1H), 2.18-2.07 (m, 1H), 2.01-1.83 (m, 3H), 1.68-1.54(m, 4H). LCMS (ESI) m/z: [M+H]⁺=780.60.

Example 19—Preparation ofN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(Compound D8)

Step 1: Preparation of tert-butylN-[8-[(8-bromo-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(i19-2)

To a mixture of 4-bromo-7-chloro-2-methyl-2,6-naphthyridin-1-one (100mg, 0.366 mmol, 1.00 equiv) and tert-butyl N-(8-aminooctyl)carbamate(268.1 mg, 1.097 mmol, 3.00 equiv) in DMSO (3.00 mL) was added K₂CO₃(505.3 mg, 3.656 mmol, 10.00 equiv). The resulting solution was stirredat 130° C. for 5 hours. The resulting solution was diluted with of EtOAc(80 mL). The resulting mixture was washed with water (3×50 mL). Theorganic layer was concentrated under reduced pressure. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:1). Fractions containing the desired compound were evaporated todryness to afford tert-butylN-[8-[(8-bromo-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(50 mg, 28.4%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=483.

Step 2: Preparation of tert-butylN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(i19-3)

To a solution of tert-butylN-[8-[(8-bromo-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(50.0 mg, 0.104 mmol, 1.00 equiv) and4-[(dimethylamino)methyl]-3,5-dimethoxyphenylboronic acid (37.2 mg,0.156 mmol, 1.50 equiv) in H₂O (0.50 mL) and dioxane (1.50 mL) was addedCs₂CO₃ (67.7 mg, 0.208 mmol, 2.00 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (7.60mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred at 90°C. for 1 hour under N₂ atmosphere. The resulting solution was dilutedwith of EtOAc (50 mL). The resulting mixture was washed with water (3×30mL). The resulting mixture was concentrated under reduced pressure. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (30:70). Fractions containing the desiredcompound were evaporated to dryness to afford tert-butylN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(30 mg, 48.5%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=596.

Step 3: Preparation of7-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,6-naphthyridin-1-one(i19-4)

To a solution of tert-butylN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]carbamate(30 mg, 0.050 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (2.00mL), and the resulting solution was stirred at 25° C. for 1 hour. Theresulting mixture was concentrated under reduced pressure to afford7-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,6-naphthyridin-1-one(35 mg, crude) as a yellow liquid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=496.

Step 4: Preparation ofN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(Compound D8)

To a solution of[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(24.1 mg, 0.073 mmol, 1.20 equiv) and HATU (46.0 mg, 0.121 mmol, 2.00equiv) in DMF (2.00 mL) were added7-[(8-aminooctyl)amino]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,6-naphthyridin-1-one(30.0 mg, 0.061 mmol, 1.00 equiv) and DIEA (39.1 mg, 0.303 mmol, 5.00equiv). The resulting solution was stirred at 25° C. for 2 hours. Thecrude product was purified by preparative HPLC (conditions: XSelect CSHPrep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% Bin 8 minutes; 254 nm; Rt: 7.12 minutes) to affordN-[8-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(12 mg, 24.5%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.41(s, 1H), 7.80 (dd, J=8.4, 7.4 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.43 (d,J=9.1 Hz, 2H), 7.15 (s, 1H), 6.90 (s, 2H), 5.13 (dd, J=12.4, 5.4 Hz,1H), 4.77 (s, 2H), 4.42 (s, 2H), 3.98 (s, 6H), 3.63 (s, 3H), 3.40-3.35(m, 2H), 3.30-3.21 (m, 2H), 2.92 (s, 6H), 2.90-2.82 (m, 1H), 2.80-2.65(m, 2H), 2.21-2.09 (m, 1H), 1.72-1.57 (m, 4H), 1.51-1.34 (m, 8H). LCMS(ESI) m/z: [M+H]+=810.60.

Example 20—Preparation ofN-(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide(Compound D9)

Step 1: Preparation of3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanamide (i20-2)

Using a similar procedure as described in Example 10, step 1 andsubstituting with5-([2-[2-(3,3-dihydroxypropoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(150 mg, 0.344 mmol, 1.00 equiv) and ammonium chloride (24 mg, 0.448mmol, 1.30 equiv) afforded3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanamide (122 mg, 81.5%) as a yellow solid. LCMS (ESI) m/z:[M+H]+=433.

Step 2: Preparation ofN-(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide(Compound D9)

To a solution of7-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,6-naphthyridin-1-one(50 mg, 0.129 mmol, 1.00 equiv) and3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide(55.8 mg, 0.129 mmol, 1 equiv) in dioxane (4 mL) was addedtris(dibenzylideneacetone)dipalladium(O) (11.8 mg, 0.013 mmol, 0.10equiv), cesium carbonate (84.0 mg, 0.258 mmol, 2.0 equiv) and Xantphos(14.9 mg, 0.026 mmol, 0.20 equiv), and the resulting solution wasstirred at 90° C. for 3 hours. The mixture filtered through a short padof Celite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-HPLC (conditions: SunFire C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% formicacid), Mobile Phase B: acetonitrile; Flow rate: 25 mL/minute; Gradient:9 B to 22 B in 18 minutes; 254 nm) to giveN-(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide(6 mg, 5.6%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.82 (s,1H), 8.64 (s, 1H), 7.40-7.30 (m, 2H), 6.89 (s, 2H), 6.86-6.76 (m, 2H),4.99 (dd, J=12.4, 5.4 Hz, 1H), 4.44 (s, 2H), 4.01 (s, 6H), 3.92 (t,J=5.7 Hz, 2H), 3.82-3.72 (m, 6H), 3.64 (s, 3H), 3.39 (t, J=5.0 Hz, 2H),2.93 (s, 6H), 2.88-2.61 (m, 5H), 2.29-2.18 (m, 1H). LCMS (ESI) m/z:[M+H]+=784.50.

Example 21—Preparation of4-[[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D10 Formic Acid)

Intermediate i-21-1 was prepared in a similar manner to preparation ofi19-4 in Example 19. To a stirred mixture of6-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(100 mg, 0.200 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (55.3 mg, 0.200mmol, 1.00 equiv) in dimethylformamide (2 mL) was addeddiiopropylethylamine (129.3 mg, 1.001 mmol, 5.00 equiv). After stirringovernight at 90° C., the mixture was purified by Prep-HPLC (conditions:Atlantis HILIC OBD Column, 19*150 mm, 5 μm; mobile phase: A, water (0.1%formic acid) and B, acetonitrile (12% to 21% B in 9 minutes) to afford4-[[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (4 mg, 2.5%). ¹H NMR (300 MHz, Methanol-d4) δ 9.03 (s, 1H),8.57 (br s, 0.83H, formic acid), 7.51 (t, J=7.8 Hz, 1H), 7.40 (s, 1H),7.00 (d, J=7.8 Hz, 2H), 6.83 (s, 2H), 6.50 (s, 1H), 4.96-4.90 (m, 1H),4.32 (s, 2H), 3.96 (s, 6H), 3.71-3.63 (m, 8H), 3.56 (s, 3H), 3.53-3.48(m, 2H), 3.42 (t, J=5.2 Hz, 2H), 2.85 (s, 6H), 2.78-2.57 (m, 3H), 2.00(d, J=9.2 Hz, 1H). LCMS (ESI) m/z: [M+H]⁺=756.45.

Example 22—Preparation ofN-(5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamideformic acid (Compound D11 Formic Acid)

Compound D11 was prepared in a similar manner to Example 20.N-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin dol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (8.1 mg, 6.62%) was obtained as a yellow solid. ¹H NMR (300MHz, Methanol-d4) δ 9.10 (s, 1H), 8.57 (br s, 1H, FA), 8.45 (s, 1H),7.64 (s, 1H), 7.34 (dd, J=8.6, 7.1 Hz, 1H), 6.90-6.75 (m, 4H), 4.86-4.82(m, 1H), 4.61 (s, 1H), 4.33 (s, 2H), 4.02 (s, 6H), 3.94-3.84 (m, 2H),3.77-3.71 (m, 6H), 3.65 (s, 3H), 3.36 (s, 1H), 2.85 (s, 6H), 2.75-2.66(m, 3H), 2.63-2.54 (m, 1H), 2.47-2.31 (m, 1H), 1.84-1.73 (m, 1H). LCMS(ESI) m/z: [M+H]+=784.4.

Example 23—Preparation of2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]penty-l)acetamideformic acid (Compound D12 Formic Acid)

Step 1: Preparation of tert-butyl2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]acetate(i22-1)

To a stirred solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one(514 mg, 1.344 mmol, 1.00 equiv) and tert-butyl 2-bromoacetate (393.2mg, 2.016 mmol, 1.50 equiv) in acetone was added cesium carbonate (875.8mg, 2.688 mmol, 2.00 equiv) in portions at room temperature. Theresulting mixture was stirred for 1 hour at room temperature. Theresulting mixture was filtered, and the filter cake was washed withdichloromethane (3×10 mL). The filtrate was concentrated under reducedpressure. This resulted in tert-butyl2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]acetate(600 mg, 89.9%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=497.2

Step 2: Preparation of[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]aceticacid (i22-2)

To a stirred solution of tert-butyl2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]acetate(600 mg, 1.208 mmol, 1.00 equiv) in dichloromethane was addedtrifluoroacetic acid (4 mL) dropwise at room temperature. The resultingmixture was stirred for 2 hours at room temperature. The crude productwas purified by Prep-HPLC (conditions: MeCN/water 30%) to afford[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]aceticacid (450 mg, 84.6%) as a light yellow solid. LCMS (ESI) m/z:[M+H]+=441.

Step 3: Preparation of2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)acetamideformic acid (Compound D12 Formic Acid)

Using a similar procedure as described in Example 11 and substitutingwith[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]aceticacid (100 mg, 0.227 mmol, 1.00 equiv) and4-[(5-aminopentyl)oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(122.4 mg, 0.341 mmol, 1.50 equiv) afforded2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)(methyl)amino]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)acetamideformic acid (80 mg, 42.6%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 8.56 (s, 1H), 8.51 (brs, 0.8H, formic acid), 7.78 (dd,J=8.6, 7.2 Hz, 1H), 7.48-7.42 (m, 2H), 7.25 (s, 1H), 7.14 (s, 1H), 6.89(s, 2H), 5.10 (dd, J=12.4, 5.4 Hz, 1H), 4.82 (s, 2H), 4.27 (t, J=5.9 Hz,2H), 4.08 (s, 2H), 3.94 (s, 6H), 3.66 (s, 3H), 3.40-3.36 (m, 2H), 3.28(s, 6H), 2.98 (s, 3H), 2.90-2.67 (m, 3H), 2.19-2.08 (m, 1H), 1.97-1.86(m, 2H), 1.74-1.61 (m, 4H). LCMS (ESI) m/z: [M+H]+=782.50.

Example 24—Preparation ofN-(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethoxy]propanamideformic acid (Compound D13 Formic Acid)

Compound D13 was prepared in a similar manner to Example 20.N-(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethoxy]propanamideformic acid (7 mg, 6.9%) was obtained. ¹H NMR (300 MHz, Methanol-d4) δ8.86 (d, J=0.9 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.56 (brs, 0.9H, FA),7.40 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.82 (s, 2H), 6.63 (d, J=2.2 Hz,1H), 6.54 (dd, J=8.4, 2.2 Hz, 1H), 5.05-4.97 (m, 1H), 4.33 (s, 2H), 3.98(s, 6H), 3.93 (t, J=5.6 Hz, 2H), 3.75-3.70 (m, 6H), 3.58 (s, 3H), 3.18(t, J=5.4 Hz, 2H), 2.85 (s, 6H), 2.79-2.57 (m, 5H), 2.08-1.97 (m, 1H).LCMS (ESI) m/z: [M+H]+=784.55.

Example 25—Preparation ofN-(5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanamideformic acid (Compound D14 Formic Acid)

Compound D13 was prepared in a similar manner to Example 20.N-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin-dol-5-yl]amino]ethoxy)ethoxy]propanamideformic acid (6 mg, 6.62%) was obtained as a yellow solid. ¹H NMR (300MHz, Methanol-d4) δ 9.19 (s, 1H), 8.55 (brs, 1.8H, FA), 8.51 (s, 1H),7.65 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 6.83 (s, 2H), 6.67 (d, J=2.1 Hz,1H), 6.56 (dd, J=8.4, 2.2 Hz, 1H), 5.05-4.98 (m, 1H), 4.36 (s, 2H), 4.00(s, 6H), 3.87 (t, J=5.5 Hz, 2H), 3.72-3.63 (m, 6H), 3.59 (s, 3H), 3.13(t, J=5.4 Hz, 2H), 2.90 (s, 6H), 2.83-2.60 (m, 5H), 2.11-2.00 (m, 1H).LCMS (ESI) m/z: [M+H]+=784.5.

Example 26—Preparation of4-([5-[9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D15 Formic Acid)

Step 1: Preparation of tert-butyl9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(i26-2)

To a solution of2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]benzaldehyde(100 mg, 0.283 mmol, 1.00 equiv) and tert-butyl1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (87.1 mg, 0.340 mmol,1.20 equiv) in MeOH (2.00 mL) was added NaBH₃CN (35.6 mg, 0.566 mmol,2.00 equiv), and the resulting solution was stirred at 25° C. for 2hours. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with DCM/MeOH (20:1). This resulted intert-butyl9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(110 mg, 65.5%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=594.

Step 2: Preparation of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one(i26-3)

To a solution of tert-butyl9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(100.0 mg, 0.168 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (2.00mL), and the resulting solution was stirred at 25° C. for 2 h. Theresulting mixture was concentrated under vacuum to give4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one(90 mg, crude) as a yellow solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=494.

Step 3: Preparation of4-([5-[9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D15 Formic Acid)

To a solution of5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (15.2 mg, 0.041 mmol, 1.00 equiv) and HATU (30.8 mg, 0.081 mmol,2.00 equiv), in solvent DMF (2.00 mL) was added4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one(20.0 mg, 0.041 mmol, 1.00 equiv) and DIEA (15.7 mg, 0.122 mmol, 3.00equiv), and the resulting solution was stirred at 25° C. for 2 hours.The resulting mixture was concentrated. The crude product was purifiedby preparative HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 20% B to 55% B in 8 minutes; 254 nm;R_(t): 7.12 minutes) to afford4-([5-[9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (20 mg, 52.8%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 8.56 (br s, 0.5H, FA), 8.51 (s, 1H), 7.83-7.74 (m, 1H),7.50-7.42 (m, 2H), 7.24 (d, J=3.8 Hz, 1H), 7.11 (s, 1H), 6.83 (d, J=9.2Hz, 2H), 5.12 (dd, J=12.2, 5.3 Hz, 1H), 4.33-4.22 (m, 3H), 3.93 (d,J=8.5 Hz, 7H), 3.83-3.69 (m, 3H), 3.67-3.60 (m, 5H), 3.51 (s, 2H),3.22-3.10 (m, 2H), 2.97 (s, 3H), 2.92-2.63 (m, 5H), 2.18-1.86 (m, 8H),1.83-1.69 (m, 2H). LCMS (ESI) m/z: [M+H]+=850.60.

Example 27—Preparation of4-(4-(9-(2,6-dimethoxy-4-(2-methyl-7-(methylamino)-1-oxo-1,2-dihydro-2,6-naphthyridin-4-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D16 Formic Acid)

Compound D16 was prepared in a similar manner to Example 26.4-[4-[9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(16 mg, 20.0%) was obtained as a light brown solid. ¹H NMR (400 MHz,Methanol-d4) δ 8.57 (brs, 0.6H, FA), 8.54 (d, J=4.5 Hz, 1H), 7.80 (t,J=7.9 Hz, 1H), 7.48 (dd, J=7.2, 5.0 Hz, 2H), 7.25 (d, J=1.0 Hz, 1H),7.13 (d, J=4.6 Hz, 1H), 6.83 (d, J=10.9 Hz, 2H), 5.13 (dd, J=12.5, 5.5Hz, 1H), 4.31 (t, J=5.7 Hz, 2H), 4.26-4.16 (m, 2H), 3.92 (d, J=12.1 Hz,6H), 3.75-3.69 (m, 3H), 3.65 (s, 3H), 3.60-3.48 (m, 3H), 3.24-3.02 (m,4H), 2.97 (s, 3H), 2.81-2.65 (m, 5H), 2.24-2.12 (m, 3H), 2.10-1.84 (m,3H), 1.79-1.65 (m, 1H). LCMS (ESI) m/z: [M+H]+=836.45.

Example 28—Preparation of4-(4-(4-(2,6-dimethoxy-4-(2-methyl-7-(methylamino)-1-oxo-1,2-dihydro-2,6-naphthyridin-4-yl)benzyl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D17 Formic Acid)

Compound D17 was prepared in a similar manner to Example 26.4-[4-[4-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (11.0 mg, 12.8%) was obtained as a yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.14 (s, 1H), 9.63 (s, 1H), 8.56 (brs, 0.9H, FA),7.87-7.77 (m, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.20(s, 1H), 7.13 (s, 1H), 6.98 (d, J=4.8 Hz, 1H), 6.86 (s, 2H), 5.09 (dd,J=12.7, 5.4 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.27 (dd, J=13.9, 7.8 Hz,4H), 4.07 (d, J=13.6 Hz, 1H), 3.90 (s, 6H), 3.58-3.48 (m, 4H), 3.47-3.38(m, 3H), 3.26-2.98 (m, 3H), 2.96-2.88 (m, 1H), 2.87-2.83 (m, 3H),2.65-2.55 (m, 3H), 2.09-1.95 (m, 3H). LCMS (ESI) m/z: [M+H]⁺=766.50.

Example 29—Preparation of4-(4-(9-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D18 Formic Acid)

Compound D18 was prepared in a similar manner to Example 26.4-[4-[9-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (12.7 mg) was obtained as a white solid. LCMS (ESI) m/z:[M+H]+=850.55. ¹H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 8.47 (brs,1.2H, FA), 7.80 (t, J=7.9 Hz, 1H), 7.48 (d, J=9.9 Hz, 3H), 6.89 (d,J=7.2 Hz, 2H), 6.49 (d, J=3.7 Hz, 1H), 5.13 (dd, J=12.6, 5.5 Hz, 1H),4.40 (s, 2H), 4.31 (s, 2H), 3.95 (d, J=12.5 Hz, 6H), 3.80-3.65 (m, 4H),3.60 (d, J=3.1 Hz, 3H), 3.57-3.48 (m, 2H), 3.34 (s, 4H), 3.13 (s, 6H),2.85-2.59 (m, 5H), 2.24-2.04 (m, 6H), 1.84-1.74 (m, 1H).

Example 30—Preparation of5-((5-(9-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D19 Formic Acid)

Compound D19 was prepared in a similar manner to Example 26.5-([5-[9-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (8.1 mg, 11.1%) was obtained as a white solid. LCMS (ESI)m/z: [M+H]⁺=864.55. ¹H NMR (400 MHz, Methanol-d4) δ 9.14 (d, J=1.8 Hz,1H), 8.56 (brs, 0.5H, FA), 7.80 (t, J=9.0 Hz, 1H), 7.44 (d, J=2.6 Hz,1H), 7.40 (dd, J=4.2, 2.2 Hz, 1H), 7.35-7.28 (m, 1H), 6.85 (d, J=6.7 Hz,2H), 6.49 (s, 1H), 5.15-5.06 (m, 1H), 4.31-4.11 (m, 4H), 3.94 (d, J=4.9Hz, 6H), 3.81-3.71 (m, 2H), 3.64-3.56 (m, 5H), 3.55-3.45 (m, 2H),3.25-3.00 (m, 10H), 2.94-2.82 (m, 1H), 2.81-2.66 (m, 2H), 2.62-2.45 (m,2H), 2.18-1.99 (m, 3H), 1.96-1.71 (m, 6H).

Example 31—Preparation of5-(4-(2-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D20 Formic Acid)

To a mixture of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(30.0 mg, 0.082 mmol, 1.00 equiv) in DMF (1.00 mL) was added2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(37.0 mg, 0.082 mmol, 1.00 equiv). The resulting mixture was stirred for1 hour, and NaBH(OAc)₃ (34.6 mg, 0.163 mmol, 2.00 equiv) was added. Theresulting mixture was stirred overnight at room temperature. Without anyadditional work-up, the mixture was purified by prep-HPLC (conditions:Phenomenex Gemini C6-Phenyl, 21.2*250 mm, 5 μm; Mobile Phase A: Water(0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 11%B to 17% B in 17 minutes; 254 nm; R_(T):14.2 minutes) to afford5-(4-(2-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;formate acid (9.0 mg, 13.8%) as a yellow solid. ¹H NMR (300 MHz,DMSO-d6) δ 11.09 (s, 1H), 9.45 (brs, 0.6H, FA salt), 9.05 (s, 1H), 8.14(s, 0.7H, FA), 7.75 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.34(d, J=8.9 Hz, 1H), 6.90 (s, 2H), 6.52 (d, J=6.4 Hz, 1H), 5.09 (dd,J=12.7, 5.4 Hz, 1H), 4.21 (s, 3H), 3.91 (s, 7H), 3.50 (s, 4H), 3.47-3.37(m, 4H), 3.20-3.05 (m, 9H), 3.04-2.86 (m, 4H), 2.74-2.54 (m, 3H),2.09-1.98 (m, 1H), 1.97-1.75 (m, 3H), 1.70-1.48 (m, 4H). LCMS (ESI) m/z:[M+H]+=805.55.

Example 32—Preparation of5-[4-(2-[2-[([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)(methyl)amino]ethoxy]ethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D21)

Step 1: Preparation of tert-butylN-[2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)ethyl]-N-methylcarbamate(i32-2)

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (50.00mg, 0.146 mmol, 1.00 equiv) and tert-butylN-methyl-N-[2-(2-oxoethoxy)ethyl]carbamate (47.60 mg, 0.219 mmol, 1.50equiv), in DMF (2.00 mL) was added NaBH₃CN (18.36 mg, 0.292 mmol, 2.00equiv), and the resulting solution was stirred at 25° C. for 3 hours.The resulting mixture was concentrated. The residue was applied onto asilica gel column with CH₂Cl₂/MeOH (20:1). This resulted in tert-butylN-[2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)ethyl]-N-methylcarbamate(45 mg, 56.68%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=544.50.

Step 2: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[2-(methylamino)ethoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(i32-3)

A solution of tert-butylN-[2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)ethyl]-N-methylcarbamate (45.00 mg, 0.083 mmol, 1.00 equiv) in TFA(1.00 mL) and CH₂Cl₂ (1.00 mL) was stirred at 25° C. for 1 hour. Theresulting mixture was concentrated, and the crude material was useddirectly without further purification.2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[2-(methylamino)ethoxy]ethyl]piperazin-1-yl)isoindole-1,3-dionewas obtained as a yellow solid. LCMS (ESI) m/z: [M+H]+=444.50.

Step 3: Preparation of5-[4-(2-[2-[([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)(methyl)amino]ethoxy]ethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D21)

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[2-(methylamino)ethoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(50.00 mg, 0.113 mmol, 1.00 equiv) and4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(49.70 mg, 0.135 mmol, 1.20 equiv) in DMF (2.00 mL) was added NaBH₃CN(14.17 mg, 0.225 mmol, 2.00 equiv), and the resulting solution wasstirred at 25° C. for 3 hours. The resulting mixture was concentrated.The crude product was purified by preparative HPLC (conditions: XSelectCSH Prep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to55% B in 8 minutes; 254 nm; R_(T): 7.12 minutes). This resulted in5-[4-(2-[2-[([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)(methyl)amino]ethoxy]ethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (10 mg, 18.60%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 9.04 (s, 1H), 8.14 (brs, 0.2H, FA), 7.67 (d,J=8.5 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.23 (dd, J=8.7,2.3 Hz, 1H), 6.85 (s, 2H), 6.46 (s, 1H), 5.07 (dd, J=12.9, 5.4 Hz, 1H),4.39-4.01 (m, 2H), 3.88 (s, 7H), 3.76 (s, 3H), 3.62 (t, J=5.7 Hz, 3H),3.48 (s, 5H), 3.37-3.26 (m, 4H), 3.06 (s, 6H), 2.94-2.84 (m, 1H),2.63-2.56 (m, 8H), 2.07-1.98 (m, 1H). LCMS (ESI) m/z: [M+H]+=795.45.

Example 33—Preparation5-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-4,7-dioxa-1,10-diazaundecan-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D22 Formic Acid)

Compound D22 was prepared in a similar manner to Example 21. ¹H NMR (400MHz, Methanol-d4) δ 9.06 (s, 1H), 8.55 (brs, 1.7H, FA), 7.45 (d, J=8.4Hz, 1H), 7.40 (s, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.83 (s, 2H), 6.74 (dd,J=8.4, 2.2 Hz, 1H), 6.51 (d, J=0.7 Hz, 1H), 5.03 (dd, J=12.7, 5.5 Hz,1H), 4.56 (s, 2H), 3.95 (s, 6H), 3.72-3.62 (m, 8H), 3.58-3.52 (m, 5H),3.29 (t, J=5.3 Hz, 2H), 3.13 (s, 9H), 2.95-2.81 (m, 1H), 2.79-2.61 (m,2H), 2.13-2.04 (m, 1H). LCMS (ESI) m/z: [M+H]+=770.45.

Example 34—Preparation5-([5-[9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D23 Formic Acid)

Compound D22 was prepared in a similar manner to Example 26. ¹H NMR (400MHz, Methanol-d4) δ 8.58 (brs, 1.1H, formic acid), 8.51 (s, 1H), 7.80(t, J=8.9 Hz, 1H), 7.43-7.39 (m, 1H), 7.35-7.29 (m, 1H), 7.24 (d, J=5.0Hz, 1H), 7.10 (d, J=3.2 Hz, 1H), 6.83 (d, J=8.3 Hz, 2H), 5.10 (dt,J=11.0, 5.5 Hz, 1H), 4.22 (t, J=6.2 Hz, 3H), 4.10 (s, 1H), 3.93 (d,J=6.8 Hz, 6H), 3.81-3.75 (m, 1H), 3.75-3.70 (m, 1H), 3.65 (s, 3H),3.63-3.49 (m, 4H), 3.22-3.03 (m, 4H), 2.97 (s, 3H), 2.90-2.71 (m, 3H),2.52 (dt, J=30.3, 7.1 Hz, 2H), 2.18-2.08 (m, 1H), 2.07-1.97 (m, 2H),1.96-1.69 (m, 6H). LCMS (ESI) m/z: [M+H]+=850.45.

Example 35—Preparation of4-[[2-(2-[2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D24)

Compound D24 was prepared in a similar manner to Example 21. ¹H NMR (400MHz, Methanol-d4) δ 8.44 (d, J=0.9 Hz, 1H), 7.52-7.42 (m, 1H), 7.23 (d,J=0.9 Hz, 1H), 7.07 (s, 1H), 6.97 (dd, J=18.7, 7.8 Hz, 2H), 6.83 (s,2H), 5.02-4.96 (m, 1H), 4.28-4.11 (m, 2H), 3.96 (s, 6H), 3.80-3.75 (m,4H), 3.74-3.70 (m, 4H), 3.61 (s, 3H), 3.55 (t, J=5.3 Hz, 2H), 3.47 (t,J=5.1 Hz, 2H), 2.81-2.63 (m, 9H), 2.12-2.04 (m, 1H). LCMS (ESI) m/z:[M+H]⁺=756.33.

Example 36—Preparation of4-((5-((8-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D25)

Compound D25 was prepared in a similar manner to Example 17. ¹H NMR (300MHz, Methanol-d4) δ 7.94 (s, 1H), 7.76 (dd, J=8.6, 7.2 Hz, 1H), 7.54 (s,1H), 7.46-7.40 (m, 2H), 7.24 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 5.11(d, J=10.8 Hz, 1H), 4.42 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.95 (s, 3H),3.77 (s, 3H), 3.61 (s, 3H), 3.46 (t, J=6.5 Hz, 2H), 2.94 (s, 6H),2.92-2.83 (m, 1H), 2.80-2.76 (m, 1H), 2.75-2.68 (m, 1H), 2.18-2.07 (m,1H), 2.01-1.90 (m, 2H), 1.87-1.72 (m, 4H). LCMS (ESI) m/z:[M+H]⁺=711.85.

Example 37—Preparation2-[(8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-2,6-naphthyridin-3-yl)amino]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)acetamide (Compound D26)

Compound D26 was prepared in a similar manner to Example 22. ¹H NMR (300MHz, Methanol-d4) δ 8.53 (br s, 1.3H, FA), 8.50 (s, 1H), 7.78 (dd,J=8.6, 7.2 Hz, 1H), 7.48-7.43 (m, 2H), 7.37 (s, 1H), 7.15 (s, 1H), 6.88(s, 2H), 5.10 (dd, J=12.3, 5.4 Hz, 1H), 4.81 (s, 2H), 4.27 (t, J=5.9 Hz,2H), 4.08 (s, 2H), 3.94 (s, 6H), 3.65 (s, 3H), 3.27 (s, 6H), 2.95-2.64(m, 4H), 2.19-2.07 (m, 1H), 1.96-1.87 (m, 2H), 1.79-1.58 (m, 5H). LCMS(ESI) m/z: [M+H]⁺=768.40.

Example 38—Preparation4-((5-(9-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D27 Formic Acid)

Compound D27 was prepared in a similar manner to Example 23. ¹H NMR (300MHz, Methanol-d4) δ 9.15 (s, 1H), 8.55 (brs, 1.0H, formic acid), 7.79(t, J=7.9 Hz, 1H), 7.46 (d, J=8.4 Hz, 3H), 6.87 (d, J=7.2 Hz, 2H), 6.49(s, 1H), 5.12 (dd, J=12.1, 5.4 Hz, 1H), 4.36-4.23 (m, 4H), 3.95 (d,J=6.4 Hz, 6H), 3.82-3.72 (m, 2H), 3.66-3.60 (m, 2H), 3.59 (s, 3H), 3.52(s, 2H), 3.30-3.16 (m, 4H), 3.12 (s, 6H), 2.91-2.59 (m, 5H), 2.20-2.03(m, 3H), 2.00-1.76 (m, 6H). LCMS (ESI) m/z: [M+H]+=864.40.

Example 39—Preparation of1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (Compound D28)

A solution ofN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide(60.00 mg, 0.119 mmol, 1.00 equiv) and4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(52.43 mg, 0.143 mmol, 1.20 equiv) in DMF (1.50 mL) was stirred for 20minute at room temperature. Then NaBH₃CN (14.95 mg, 0.238 mmol, 2.00equiv) was added to the reaction mixture. The resulting mixture wasstirred for 1 hour at room temperature. The crude product was purifiedby Prep-HPLC (conditions: Column, Phenomenex Gemini C6-Phenyl, 21.2*250mm, 5 μm; mobile phase, Water (0.05% FA) and ACN (5% PhaseB up to 23% in20 minutes); Detector, UV). This resulted in1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide (13.4 mg, 13.16%) as a green solid. ¹H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 9.02 (s, 1H), 8.26 (s, 0.3H, FA), 7.66(d, J=8.5 Hz, 1H), 7.55 (s, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.23 (dd,J=8.7, 2.3 Hz, 1H), 7.07 (t, J=5.9 Hz, 1H), 6.75 (s, 2H), 6.47 (s, 1H),5.07 (dd, J=12.9, 5.4 Hz, 1H), 4.01 (q, J=7.2 Hz, 1H), 3.81 (s, 6H),3.62 (s, 2H), 3.49-3.45 (m, 5H), 3.44-3.39 (m, 7H), 3.06 (s, 8H),2.94-2.82 (m, 1H), 2.59 (d, J=16.8 Hz, 3H), 2.55 (s, 2H), 2.42 (t, J=6.7Hz, 2H), 2.07-1.97 (m, 1H). LCMS (ESI) m/z: [M+H]+=856.34.

Example 40—Preparation4-[2-[4-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D29)

Compound D27 was prepared in a similar manner to Example 23. ¹H NMR (300MHz, Methanol-d4) δ 8.55 (d, J=0.9 Hz, 1H), 7.79 (dd, J=8.5, 7.3 Hz,1H), 7.52 (d, J=7.2 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.24 (d, J=0.9 Hz,1H), 7.10 (s, 1H), 6.81 (s, 2H), 5.16-5.07 (m, 3H), 4.06 (s, 2H), 3.91(s, 6H), 3.83-3.69 (m, 4H), 3.65 (s, 3H), 3.00-2.85 (m, 7H), 2.83-2.68(m, 3H), 2.21-2.07 (m, 1H). LCMS (ESI) m/z: [M+H]+=738.45.

Example 41—Preparation of5-(4-[2-[1-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)piperidin-4-yl]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D30 Formic Acid)

Step 1: Preparation of4-bromo-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one (i41-2)

To a stirred solution of4-bromo-7-chloro-2-methyl-2,6-naphthyridin-1-one (200.00 mg, 0.731 mmol,1.00 equiv) and methanamine hydrochloride (493.73 mg, 7.312 mmol, 10.00equiv) in DMSO (15.00 mL) was added K₂CO₃ (2021.21 mg, 14.625 mmol,20.00 equiv). The resulting mixture was stirred for 16 hours at 130° C.under nitrogen atmosphere. The resulting mixture was diluted with water(50 mL). The aqueous layer was extracted with EtOAc (4×15 mL). Theresulting mixture was washed with brine (15 mL). The resulting mixturewas concentrated under reduced pressure to afford4-bromo-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one (100 mg, 51.01%)as a yellow solid.

Step 2: Preparation of 2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]benzaldehyde (i85-3)

To a stirred solution of4-bromo-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one (100.00 mg,0.373 mmol, 1.00 equiv) and 4-formyl-3,5-dimethoxyphenylboronic acid(93.99 mg, 0.448 mmol, 1.20 equiv) in 1,4-dioxane/H2O (4:1) (5.00 mL)was added cesium carbonate (243.80 mg, 0.746 mmol, 2.00 equiv) andPd(dppf)Cl₂ (27.29 mg, 0.037 mmol, 0.10 equiv). The resulting mixturewas stirred for 16 hours at 90° C. under nitrogen atmosphere. Theresulting mixture was diluted with water (15 mL). The aqueous layer wasextracted with EtOAc (3×20 mL). The organic layers were concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with DCM:MeOH (40:1 to 10:1) to afford2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]benzaldehyde (30 mg, 22.76%) as a yellow solid.

Step 3: Preparation of5-(4-[2-[1-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)piperidin-4-yl]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D30 Formic Acid)

A solution of2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]benzaldehyde(25.00 mg, 0.071 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(32.09 mg, 0.071 mmol, 1.00 equiv) in DMF (1.00 mL) was stirred for 1hour at 20° C. under nitrogen atmosphere. To the above mixture was addedNaBH(OAc)₃ (29.99 mg, 0.141 mmol, 2 equiv). The resulting mixture wasstirred for additional 1 hour at 20° C. The crude product was purifiedby Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 9 B to 16 B in 13 minutes; 254 nm; R_(T):11.47 minutes) to afford5-(4-[2-[1-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)piperidin-4-yl]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(11.7 mg, 20.91%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.08(s, 1H), 8.54 (s, 1H), 8.15 (s, 0.9H, FA), 7.68 (d, J=8.4 Hz, 1H), 7.34(d, J=2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.93(d, J=5.1 Hz, 1H), 6.78 (s, 2H), 5.07 (dd, J=12.8, 5.4 Hz, 1H), 3.85 (s,9H), 3.53 (s, 4H), 3.44-3.42 (m, 5H), 3.12-3.08 (m, 2H), 2.91-2.87 (m,1H), 2.85 (d, J=4.9 Hz, 3H), 2.64-2.53 (m, 3H), 2.37-2.32 (m, 3H),2.04-1.99 (m, 1H), 1.77-1.70 (m, 2H), 1.47-1.37 (m, 3H), 1.32-1.23 (m,3H). LCMS (ESI) m/z: [M+H]+=791.50.

Example 42—Preparation of4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-4,7-dioxa-1,10-diazaundecan-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D31)

Step 1: Preparation of tert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate(i42-2)

To a stirred solution of6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(335.0 mg, 0.864 mmol, 1.00 equiv) and tert-butylN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (643.4 mg, 2.591 mmol,3.00 equiv) in DMSO (2 mL) was added K₂CO₃ (238.7 mg, 1.727 mmol, 2.00equiv) at room temperature. The resulting mixture was stirred overnightat 130 degrees C. The mixture was allowed to cool down to roomtemperature. The resulting mixture was filtered, and the filter cake waswashed with CH₂Cl₂ (2×3 mL). The filtrate was concentrated under reducedpressure. The residue was purified by reverse flash chromatography(conditions: column, C18 silica gel; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 40% B in 15min; detector, 254 nm) to afford tert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate (380 mg, 73.36%) as a yellow oil. LCMS (ESI) m/z:[M+H]⁺=600.

Step 2: Preparation of tert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate(i42-3)

To a stirred solution/mixture of tert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate(190.0 mg, 0.317 mmol, 1.00 equiv) and K₂CO₃ (87.6 mg, 0.634 mmol, 2equiv) in acetone (3 mL) was added dimethyl sulfate (44.0 mg, 0.348mmol, 1.10 equiv) at room temperature. The resulting mixture was stirredovernight at room temperature. The reaction was quenched with water atroom temperature. The aqueous layer was extracted withCH₂Cl₂/isopropanol (3×5 mL). The combined organic layers were washedwith brine (1×10 mL) and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure to affordtert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate(95.00 mg, 48.86%) as a yellow oil. The crude product was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]⁺=614.

Step 3: Preparation of 3,3,3-tritfluoropropanoic acid;6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(i42-4)

To a stirred solution of tert-butylN-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate(75.00 mg, 0.122 mmol, 1.00 equiv) in dichloromethane (3 mL) was addedTFA (1 mL) dropwise at room temperature. The resulting mixture wasconcentrated under vacuum to afford 3,3,3-trifluoropropanoic acid;6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(103 mg, crude) as yellow oil. The crude product was used in the nextstep directly without further purification. LCMS (ESI) m/z: [M+H]⁺=514.

Step 4: Preparation of4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-4,7-dioxa-1,10-diazaundecan-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D31)

To a stirred solution of6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (68.00 mg,0.132 mmol, 1.00 equiv) in DMF (1 mL) was added2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (34.6 mg, 0.125mmol, 0.95 equiv) and DIEA (85.6 mg, 0.662 mmol, 5.00 equiv) at roomtemperature. The resulting mixture was stirred for overnight at 80degrees C. The crude product was purified by Prep-HPLC (conditions:Xselect CSH F-Phenyl OBD Column 19*150 mm 5 um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 9 B to19 B in 12 min; 254 nm; R_(t):12.63 minutes) to afford4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-4,7-dioxa-1,10-diazaundecan-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(3.2 mg, 3.14%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.96(s, 1H), 7.54-7.46 (m, 2H), 6.99 (dd, J=15.8, 7.7 Hz, 2H), 6.84 (s, 2H),6.74 (s, 1H), 4.96-4.94 (m, 1H), 4.57 (s, 2H), 3.97 (s, 6H), 3.77-3.69(m, 8H), 3.59-3.53 (m, 5H), 3.41 (t, J=5.2 Hz, 2H), 3.17-3.11 (m, 9H),2.83-2.53 (m, 3H), 2.04-1.95 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=770.50.

Example 43—Preparation of Compounds D32-D184

In analogy to the procedures described in the examples above, compoundsD32-D184 were prepared using the appropriate starting materials

Compound No. LCMS ¹H NMR D32 856.34 ¹H NMR (400 MHz, DMSO-d6) δ 11.08(s, 1H), 9.02 (s, 1H), 8.26 (s, 0.3H, FA), 7.66 (d, J = 8.5 Hz, 1H),7.55 (s, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.7, 2.3 Hz, 1H),7.07 (t, J = 5.9 Hz, 1H), 6.75 (s, 2H), 6.47 (s, 1H), 5.07 (dd, J =12.9, 5.4 Hz, 1H), 4.01 (q, J = 7.2 Hz, 1H), 3.81 (s, 6H), 3.62 (s, 2H),3.49-3.45 (m, 5H), 3.44-3.39 (m, 7H), 3.06 (s, 8H), 2.94-2.82 (m, 1H),2.59 (d, J = 16.8 Hz, 3H), 2.55 (s, 2H), 2.42 (t, J = 6.7 Hz, 2H),2.07-1.97 (m, 1H). D33 836.6 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H),9.03 (d, J = 1.6 Hz, 1H), 8.20 (s, 0.8H, FA), 7.82 (dd, J = 8.3, 2.3 Hz,1H), 7.58 (s, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 8.3, 2.3 Hz,1H), 6.75 (s, 2H), 6.43 (s, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H),4.38-4.17 (m, 3H), 3.98-3.88 (m, 1H), 3.79 (s, 6H), 3.77-3.65 (m, 6H),3.65-3.60 (m, 3H), 3.26 (s, 2H), 3.05 (s, 6H), 2.99-2.79 (m, 4H),2.63-2.52 (m, 4H), 2.29-2.12 (m, 1H), 2.10-1.99 (m, 1H), 1.54-1.29 (m,2H). D34 834.37 ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.04 (s, 1H),7.82 (dd, J = 8.5, 7.3 Hz, 1H), 7.69 (s, 1H), 7.59-7.50 (m, 2H), 7.45(d, J = 7.2 Hz, 1H), 6.73 (s, 2H), 6.46 (s, 1H), 5.08 (dd, J = 12.9, 5.4Hz, 1H), 4.21 (t, J = 6.4 Hz, 2H), 3.80 (s, 6H), 3.48 (s, 5H), 3.07 (s,9H), 2.94-2.81 (m, 1H), 2.62-2.54 (m, 2H), 2.04 (s, 4H), 1.91 (s, 5H),1.82-1.72 (m, 2H), 1.53-1.39 (m, 4H). D35 847.35 1H-NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H, FA), 7.64 (t, J =5.8 Hz, 1H), 7.61-7.55 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J =7.0 Hz, 1H), 6.76 (s, 2H), 6.52 (t, J = 5.9 Hz, 1H), 6.47 (s, 1H), 5.05(dd, J = 12.8, 5.4 Hz, 1H), 3.82 (s, 6H), 3.60 (s, 2H), 3.48 (s, 3H),3.31-3.25 (m, 2H), 3.06 (s, 6H), 3.05- 3.00 (m, 2H), 2.93-2.85 (m, 1H),2.62-2.52 (m, 4H), 2.16 (s, 3H), 2.06-1.99 (m, 1H), 1.85 (s, 6H),1.63-1.54 (m, 2H), 1.49-1.40 (m, 2H), 1.36-1.26 (m, 2H). D36 848.41H-NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H,FA), 7.81 (dd, J = 8.5, 7.2 Hz, 1H), 7.66 (t, J = 5.8 Hz, 1H), 7.57 (s,1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.76 (s, 2H),6.47 (s, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H),3.82 (s, 6H), 3.63 (s, 2H), 3.48 (s, 3H), 3.09-3.01 (m, 8H), 2.94-2.83(m, 1H), 2.63-2.52 (m, 4H), 2.18 (s, 3H), 2.06- 1.98 (m, 1H), 1.86 (s,6H), 1.77 (t, J = 6.9 Hz, 2H), 1.53-1.38 (m, 4H). D37 875.7 ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 9.03 (s, 1H), 8.30 (s, 1H, FA), 7.59-7.51(m, 2H), 7.19-7.09 (m, 2H), 7.03 (d, J = 7.0 Hz, 1H), 6.74 (s, 2H), 6.60(t, J = 5.8 Hz, 1H), 6.46 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.97(t, J = 7.5 Hz, 1H), 3.80 (s, 6H), 3.63- 3.55 (m, 6H), 3.54-3.51 (m,2H), 3.48-3.45 (m, 6H), 3.44- 3.42 (m, 5H), 3.06 (s, 8H), 2.93-2.83 (m,1H), 2.62-2.54 (m, 2H), 2.06-1.97 (m, 1H). D38 848.35 1H-NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 9.03 (s, 1H), 8.17 (s, 1H, FA), 7.83 (d, J =8.3 Hz, 1H), 7.67 (t, J = 5.8 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 2.3Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 6.76 (s, 2H), 6.47 (s, 1H),5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 3.82 (s, 6H),3.62 (s, 2H), 3.48 (s, 3H), 3.09-3.02 (m, 8H), 2.94-2.84 (m, 1H),2.64-2.53 (m, 4H), 2.18 (s, 3H), 2.10- 2.01 (m, 1H), 1.87 (s, 6H),1.80-1.72 (m, 2H), 1.52-1.35 (m, 4H). D39 847.4 1H-NMR (400 MHz,DMSO-d6) δ 11.06 (s, 1H), 9.04 (s, 1H), 8.19 (s, 1H, FA), 7.64 (t, J =5.8 Hz, 1H), 7.56 (d, J = 9.5 Hz, 2H), 7.10 (t, J = 5.2 Hz, 1H), 6.94(d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.5, 2.1 Hz, 1H), 6.75 (s, 2H), 6.47(s, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 3.81 (s, 6H), 3.57 (s, 2H),3.48 (s, 3H), 3.17-3.11 (m, 2H), 3.06 (s, 6H), 3.05-3.01 (m, 2H),2.92-2.83 (m, 1H), 2.61-2.52 (m, 4H), 2.15 (s, 3H), 2.01-1.95 (m, 1H),1.85 (s, 6H), 1.62-1.53 (m, 2H), 1.49- 1.40 (m, 2H), 1.39-1.30 (m, 2H).D40 834.37 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.04 (s, 1H), 7.84(d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.36 (d,J = 8.5 Hz, 1H), 6.73 (s, 2H), 6.50 (d, J = 31.5 Hz, 1H), 5.12 (dd, J =13.1, 5.3 Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 3.80 (s, 6H), 3.48 (s, 5H),3.07 (s, 8H), 2.95-2.84 (m, 1H), 2.70-2.59 (m, 2H), 2.31-2.18 (m, 1H),2.04 (s, 4H), 1.91 (s, 5H), 1.82-1.70 (m, 2H), 1.54-1.32 (m, 4H). D41793.55 ¹H NMR (300 MHz, Methanol-d4) δ 9.15 (s, 1H), 8.43 (s, 2H. FA).72 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.28(dd, J = 8.6, 2.3 Hz, 1H), 7.12 (s, 1H), 7.07 (dd, J = 10.0, 1.4 Hz,1H), 6.44 (d, J = 0.7 Hz, 1H), 5.10 (dd, J = 12.4, 5.4 Hz, 1H), 4.38 (s,2H), 4.02 (s, 3H), 3.64-3.49 (m, 9H), 3.19-3.08 (m, 8H), 2.92-2.68 (m,7H), 2.66-2.55 (m, 2H), 2.18-1.99 (m, 3H), 1.83-1.49 (m, 5H). D42 846.5¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.04 (s, 1H), 8.18 (s, 1H,FA), 7.84 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.35-7.26 (m, 2H), 6.80 (s,2H), 6.47 (s, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 5.07- 4.98 (m, 1H),3.91 (s, 2H), 3.84 (d, J = 1.8 Hz, 6H), 3.68 (s, 2H), 3.49 (s, 4H),3.45-3.40 (m, 3H), 3.07 (s, 7H), 2.95-2.84 (m, 1H), 2.76-2.58 (m, 5H),2.58-2.53 (m, 3H), 2.09-1.99 (m, 1H), 1.92- 1.82 (m, 2H), 1.67-1.44 (m,4H). D43 777.35 ¹H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.46-7.36 (m, 2H), 6.85 (s,2H), 6.49 (s, 1H), 5.12 (dd, J = 12.6, 5.4 Hz, 1H), 4.23 (s, 2H),4.13-4.05 (m, 1H), 3.96 (s, 6H), 3.92-3.88 (m, 1H), 3.87-3.80 (m, 5H),3.79- 3.72 (m, 3H), 3.69-3.64 (m, 1H), 3.59 (s, 3H), 3.51-3.44 (m, 1H),3.19-3.14 (m, 2H), 3.14-3.07 (m, 7H), 2.94-2.84 (m, 1H), 2.81- 2.68 (m,2H), 2.60-2.48 (m, 1H), 2.19-2.07 (m, 2H). D44 791.4 ¹H NMR (300 MHz,Methanol-d4) δ 9.14 (s, 1H, FA), 8.52 (s, 2H), 7.80 (d, J = 8.3 Hz, 1H),7.50 (s, 1H), 7.43-7.33 (m, 2H), 6.81 (s, 2H), 6.46 (s, 1H), 5.11 (dd, J= 12.4, 5.4 Hz, 1H), 4.09 (s, 3H), 3.92 (s, 7H), 3.91-3.69 (m, 9H), 3.58(s, 3H), 3.10 (s, 7H), 2.91-2.74 (m, 5H), 2.60-2.42 (m, 1H), 2.21-1.98(m, 4H), 1.41-1.30 (m, 1H). D45 735.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.12(s, 1H), 9.01 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.45-7.41 (m, 2H), 7.35(dd, J = 8.3, 2.3 Hz, 1H), 6.16-6.07 (m, 3H), 5.12 (dd, J = 12.9, 5.4Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 3.71 (s, 3H), 3.44 (s, 3H), 3.30-3.24(m, 3H), 3.07 (s, 2H), 3.03 (s, 6H), 2.95-2.84 (m, 1H), 2.67-2.57 (m,3H), 2.09- 2.01 (m, 1H), 1.82-1.71 (m, 2H), 1.61-1.49 (m, 2H), 1.48-1.40(m, 2H), 1.47 (s, 6H). D46 816.5 ¹H NMR (400 MHz, Methanol-d4) δ 9.13(s, 1H), 8.56 (s, 1H, fa), 7.82 (d, J = 8.3 Hz, 1H), 7.31-7.23 (m, 3H),6.19 (d, J = 4.5 Hz, 3H), 5.13 (s, 1H), 4.98-4.96 (m, 1H), 4.62 (s, 4H),3.78 (s, 3H), 3.56 (s, 3H), 3.37 (s, 1H), 3.15-3.13 (m, 1H), 3.10 (s,6H), 2.94- 2.83 (m, 4H), 2.80-2.67 (m, 4H), 2.64-2.56 (m, 2H), 2.18-2.10(m, 1H), 2.08-2.03 (m, 3H), 1.98-1.85 (m, 4H), 1.83-1.67 (m, 4H),1.57-1.44 (m, 2H). D47 735.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H),9.01 (s, 1H), 7.81 (dd, J = 8.5, 7.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H),7.44 (t, J = 3.6 Hz, 2H), 6.15-6.07 (m, 3H), 5.08 (dd, J = 12.9, 5.4 Hz,1H), 4.21 (t, J = 6.4 Hz, 2H), 3.71 (s, 3H), 3.44 (s, 3H), 3.32-3.22 (m,3H), 3.09-3.05 (m, 2H), 3.03 (s, 6H), 2.93-2.83 (m, 1H), 2.68-2.55 (m,3H), 2.07-1.98 (m, 1H), 1.77 (p, J = 6.5 Hz, 2H), 1.59-1.45 (m, 4H),1.37 (s, 6H). D48 776.04 ¹H NMR (300 MHz, Methanol-d4) δ 9.17 (s, 1H),8.43 (s, 3H, FA), 8.37 (s, 1H), 7.75-7.66 (m, 2H), 7.50 (s, 1H), 7.41(s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.34 (s, 1H), 5.10 (dd, J = 12.3, 5.4Hz, 1H), 4.50 (s, 2H), 4.01 (s, 3H), 3.71-3.52 (m, 10H), 3.19-3.09 (m,8H), 2.96-2.82 (m, 1H), 2.79-2.71 (m, 5H), 2.61 (t, J = 7.6 Hz, 2H),2.18-2.01 (m, 3H), 1.81-1.59 (m, 5H). D49 789.4 D50 803.5 ¹H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 9.04 (s, 1H), 8.21 (s, 2H, FA), 7.64 (d,J = 8.3 Hz, 1H), 7.58 (s, 1H), 6.80-6.75 (m, 3H), 6.64 (dd, J = 8.4, 2.1Hz, 1H), 6.47 (s, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H), 3.83 (d, J = 1.3Hz, 8H), 3.74 (s, 4H), 3.59 (s, 2H), 3.49 (s, 3H), 3.17 (s, 2H), 3.08(s, 6H), 2.93-2.84 (m, 1H), 2.66-2.53 (m, 3H), 2.48-2.42 (m, 2H), 2.29(s, 4H), 2.05-1.96 (m, 1H), 1.79- 1.68 (m, 4H). D51 789.65 D52 777.5 ¹HNMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.04 (s, 1H), 8.16 (s, 1H, FA),7.68 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.25(d, J = 8.9 Hz, 1H), 6.77 (s, 2H), 6.49 (s, 1H), 5.07 (dd, J = 12.6, 5.3Hz, 1H), 3.82 (s, 7H), 3.63-3.60 (m, 1H), 3.48 (s, 4H), 3.45-3.39 (m,5H), 3.08 (s, 6H), 3.01-2.88 (m, 3H), 2.64- 2.55 (m, 5H), 2.23-2.13 (m,2H), 2.06-1.96 (m, 1H), 1.78-1.69 (m, 2H), 1.51-1.35 (m, 2H). D53 777.3¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.04 (s, 1H), 7.66 (d, J =8.6 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.7,2.3 Hz, 1H), 6.75 (s, 2H), 6.49 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz,1H), 4.05 (d, J = 12.8 Hz, 2H), 3.81 (s, 6H), 3.56 (s, 2H), 3.48 (s,3H), 3.28-3.20 (m, 2H), 3.07 (s, 6H), 3.01-2.83 (m, 3H), 2.64- 2.53 (m,3H), 2.48-2.41 (m, 6H), 2.06-1.96 (m, 1H), 1.83 (d, J = 12.3 Hz, 2H),1.51-1.36 (m, 2H). D54 846.8 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),9.04 (s, 1H), 8.19 (s, 2H, FA), 7.83 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H),7.33-7.24 (m, 2H), 6.79 (s, 2H), 6.49 (s, 1H), 5.12 (dd, J = 12.9, 5.4Hz, 1H), 4.99 (p, J = 6.9 Hz, 1H), 3.83 (s, 6H), 3.71 (s, 2H), 3.48 (s,3H), 3.08 (s, 6H), 3.00-2.83 (m, 3H), 2.66-2.55 (m, 2H), 2.47-2.23 (m,8H), 2.15-2.00 (m, 3H), 1.85-1.75 (m, 2H), 1.71-1.51 (m, 7H), 1.24- 1.08(m, 2H). D55 860.75 ¹H NMR (400 MHz, Methanol-d4) δ 9.16 (s, 1H), 8.56(s, 1H, FA), 7.82 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.30(d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.3, 2.3 Hz, 1H), 6.86 (s, 2H), 6.51(s, 1H), 5.12 (dd, J = 12.6, 5.5 Hz, 1H), 5.01-4.93 (m, 1H), 4.18 (s,2H), 3.94 (d, J = 2.2 Hz, 6H), 3.64-3.57 (m, 5H), 3.54 (s, 2H), 3.48-3.34 (m, 4H), 3.13 (s, 6H), 2.97-2.84 (m, 3H), 2.81-2.71 (m, 2H),2.64-2.54 (m, 2H), 2.19-2.10 (m, 1H), 2.07-2.01 (m, 2H), 2.00- 1.95 (m,1H), 1.93-1.85 (m, 2H), 1.79-1.63 (m, 4H). D56 817.4 ¹H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 9.04 (s, 1H), 8.21 (s, 1H, FA), 7.68 (d, J =8.5 Hz, 1H), 7.58 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.6,2.3 Hz, 1H), 6.76 (s, 2H), 6.48 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz,1H), 3.82 (s, 6H), 3.58 (s, 3H), 3.48 (s, 3H), 3.46-3.38 (m, 5H), 3.07(s, 6H), 2.94-2.84 (m, 1H), 2.72- 2.64 (m, 1H), 2.63-2.53 (m, 2H),2.41-2.29 (m, 6H), 2.06-1.98 (m, 1H), 1.96-1.87 (m, 2H), 1.59-1.50 (m,4H), 1.47 (s, 2H). D57 791.4 ¹H NMR (300 MHz, DMSO) δ 11.09 (s, 1H),9.04 (s, 1H), 8.23 (s,1H, FA), 7.68 (d, 1H), 7.58 (s, 1H), 7.33 (d, 1H),7.25 (dd, 1H), 6.76 (s, 2H), 6.49 (s, 1H), 5.08 (dd, 1H), 3.81 (s, 6H),3.56 (s, 2H), 3.48 (s, 3H), 3.45-3.40 (m, 4H), 3.07 (s, 6H), 2.87 (d,3H), 2.64- 2.53 (m, 2H), 2.45 (s, 4H), 2.20-1.98 (m, 5H), 1.66 (d, 2H),1.52- 1.45 (m, 1H), 1.21-1.99 (m, 2H). D58 749.74 D59 762.26 D60 803.3D61 748.47 D62 776.4 D63 746.44 D64 774.16 D65 786.55 ¹H NMR (400 MHz,DMSO-d6) δ 11.15 (s, 1H), 9.03 (s, 1H), 8.20 (s, 1H FA), 7.97-7.79 (m,3H), 7.58 (s, 1H), 6.76 (s, 2H), 6.46 (s, 1H), 5.17 (dd, J = 12.8, 5.4Hz, 1H), 3.81 (s, 6H), 3.63 (d, J = 15.9 Hz, 4H), 3.48 (s, 3H), 3.06 (s,6H), 2.95-2.85 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.65-2.55 (m, 2H),2.50-2.35 (m, 6H), 2.14-1.99 (m, 1H), 1.59-1.51 (m, 6H). D66 803.45 ¹HNMR (300 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H),7.45 (s, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.92-6.83 (m, 3H), 6.48 (s, 1H),5.08 (dd, J = 12.4, 5.4 Hz, 1H), 4.51 (s, 2H), 4.32-4.17 (m, 6H),4.13-4.03 (m, 2H), 3.97 (s, 6H), 3.74-3.64 (m, 3H), 3.61- 3.52 (m, 5H),3.13 (s, 6H), 2.94-2.67 (m, 3H), 2.35 (t, J = 6.9 Hz, 2H), 2.17-2.06 (m,1H). D67 818.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.04 (s, 1H),8.18 (s, 1H, FA), 7.83 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.36-7.20 (m,2H), 6.83 (s, 2H), 6.47 (s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.98(p, J = 7.0 Hz, 1H), 4.03 (s, 2H), 3.89-3.76 (m, 8H), 3.53-3.36 (m, 6H),3.08 (s, 6H), 2.96-2.83 (m, 1H), 2.80-2.70 (m, 1H), 2.64- 2.53 (m, 3H),2.48-2.33 (m, 4H), 2.28 (s, 2H), 2.09-2.00 (m, 1H), 1.87-1.75 (m, 2H),1.67-1.50 (m, 4H). D68 734.71 ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H),9.45 (s, 1H), 8.72 (d, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.55(d, J = 5.7 Hz, 1H), 6.84 (s, 2H), 5.14 (d, J = 13.2 Hz, 1H), 4.98 (s,2H), 4.35 (s, 2H), 3.91-3.71 (m, 6H), 3.59 (s, 3H), 3.03-2.78 (m, 1H),2.73 (s, 2H), 2.67-2.49 (m, 1H), 2.05 (s, 2H). D69 749.52 D70 694.5 D71752 ¹H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.04 (s, 1H), 8.18 (s,0H, FA)7.80 (dd, J = 8.5, 7.2 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J = 8.6Hz, 1H), 7.48-7.41 (m, 1H), 6.74 (s, 2H), 6.49 (s, 1H), 5.09 (dd, J =12.9, 5.4 Hz, 1H), 4.28 (dd, J = 9.9, 5.2 Hz, 1H), 4.12- 4.02 (m, 1H),3.80 (s, 6H), 3.53 (s, 2H), 3.48 (s, 3H), 3.07 (s, 6H), 3.03-2.76 (m,3H), 2.64-2.54 (m, 6H), 2.40 (s, 3H), 2.08-1.98 (m, 1H), 1.11 (d, J =6.6 Hz, 3H). D72 772.4 ¹H NMR (300 MHz, DMSO-d6) δ 9.04 (s, 1H),7.99-7.90 (m, 3H), 7.57 (s, 1H), 6.86 (s, 2H), 6.44 (s, 1H), 5.16 (dd, J= 12.9, 5.3 Hz, 1H), 4.29 (d, J = 19.7 Hz, 6H), 3.88 (s, 6H), 3.48 (s,6H), 3.06 (s, 6H), 2.92-2.80 (m, 1H), 2.77-2.55 (m, 3H), 2.14-2.00 (m,1H), 1.22 (s, 6H). D73 800.5 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H),9.03 (s, 1H), 8.22 (s, 1H, FA), 7.97-7.88 (m, 1H), 7.88-7.79 (m, 2H),7.56 (s, 1H), 6.75 (s, 2H), 6.45 (s, 1H), 5.16 (dd, J = 12.8, 5.4 Hz,1H), 3.80 (s, 6H), 3.69 (s, 3H), 3.48 (s, 5H), 3.14-2.96 (m, 11H),2.93-2.87 (m, 1H), 2.69-2.67(m, 1H), 2.63-2.58 (m, 1H), 2.13-2.00 (m,1H), 1.65 (s, 4H), 1.41 (s, 6H). D74 793.3 ¹H NMR (300 MHz, Methanol-d4)δ 9.15 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.02 (d, J = 2.2Hz, 1H), 6.92-6.83 (m, 3H), 6.48 (s, 1H), 5.08 (dd, J = 12.4, 5.4 Hz,1H), 4.51 (s, 2H), 4.32-4.17 (m, 6H), 4.13-4.03 (m, 2H), 3.97 (s, 6H),3.74-3.64 (m, 3H), 3.61- 3.52 (m, 5H), 3.13 (s, 6H), 2.94-2.67 (m, 3H),2.35 (t, J = 6.9 Hz, 2H), 2.17-2.06 (m, 1H). D75 861.43 ¹H NMR (300 MHz,DMSO-d6) δ 11.12 (s, 1H), 9.23 (s, 2H, TFA), 9.06 (s, 1H), 7.86 (d, J =8.2 Hz, 1H), 7.60 (s, 1H), 7.36-7.25 (m, 2H), 6.92 (s, 2H), 6.51 (s,1H), 5.17-4.98 (m, 2H), 4.22 (s, 2H), 3.91 (s, 6H), 3.54-3.19 (m, 9H),3.09 (s, 8H), 2.95-2.84 (m, 2H), 2.71-2.54 (m, 3H), 2.46-2.39 (m, 1H),2.25-2.12 (m, 1H), 2.06- 1.65 (m, 11H), 1.20 (d, J = 6.7 Hz, 3H). D76752 ¹H NMR (400 MHz, DMSO-d6, D2O) δ 9.01 (s, 1H), 7.84 (d, J = 8.3 Hz,1H), 7.53 (d, J = 3.3 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.37 (dd, J =8.3, 2.2 Hz, 1H), 6.83 (s, 2H), 6.47 (s, 1H), 5.08 (dd, J = 12.9, 5.5Hz, 1H), 5.04-4.95 (m, 1H), 4.23 (s, 2H), 3.85 (s, 6H), 3.50- 3.42 (m,4H), 3.37-3.09 (m, 5H), 3.04 (s, 8H), 2.96-2.78 (m, 5H), 2.65-2.57 (m,1H), 2.08-1.99 (m, 1H), 1.27 (d, J = 6.0 Hz, 3H). D77 752 ¹H NMR (400MHz, DMSO-d6, D2O) δ 9.00 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.51 (s,1H), 7.46 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.4, 2.3 Hz, 1H), 6.82 (s,2H), 6.48 (s, 1H), 5.06 (dd, J = 12.9, 5.5 Hz, 1H), 4.31-4.23 (m, 4H),3.84 (s, 6H), 3.56-3.49 (m, 1H), 3.46 (s, 3H), 3.41-3.14 (m, 8H), 3.03(s, 6H), 2.87-2.77 (m, 1H), 2.70-2.57 (m, 2H), 2.09-2.01 (m, 1H), 1.25(d, J = 6.7 Hz, 3H) D78 766.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),9.04 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.51-7.37 (m, 2H),6.77 (s, 2H), 6.49 (s, 1H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 3.82 (s,6H), 3.65 (s, 2H), 3.51 (s, 5H), 3.07 (s, 6H), 2.93-2.84 (m, 1H), 2.59(d, J = 11.6 Hz, 10H), 2.06 (dd, J = 10.9, 5.3 Hz, 1H), 1.35 (s, 6H).D79 872.4 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.02 (s, 1H), 8.15(s, 0H, FA)7.84 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.34-7.27 (m, 2H),6.78 (s, 2H), 6.22 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.03 (t, J= 6.8 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.84 (d, J = 2.1 Hz, 6H), 3.76(s, 2H), 3.49 (s, 3H), 3.44 (s, 6H), 3.07-2.97 (m, 2H), 2.94- 2.85 (m,1H), 2.66-2.53 (m, 3H), 2.45-2.30 (m, 4H), 2.09-2.01 (m, 1H), 1.92-1.83(m, 2H), 1.67-1.47 (m, 8H). D80 858.45 ¹H NMR (300 MHz, DMSO-d6) δ 11.12(s, 1H), 9.02 (s, 1H), 8.18 (s, 1H, FA), 7.83 (d, J = 8.2 Hz, 1H), 7.60(s, 1H), 7.34-7.24 (m, 2H), 6.76 (s, 2H), 6.21 (s, 1H), 5.12 (dd, J =12.8, 5.4 Hz, 1H), 4.98 (p, J = 6.4 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H),3.83 (s, 6H), 3.70 (s, 2H), 3.48 (s, 3H), 3.02-2.80 (m, 4H), 2.67-2.59(m, 1H), 2.47- 2.39 (m, 3H), 2.37-2.22 (m, 7H), 2.14-2.01 (m, 3H),1.87-1.75 (m, 2H), 1.71-1.48 (m, 7H), 1.22-1.03 (m, 2H). D81 766.35 ¹HNMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.04 (s, 1H), 7.76 (t, J = 7.8Hz, 1H), 7.65-7.56 (m, 2H), 7.52 (d, J = 7.1 Hz, 1H), 6.79 (s, 2H), 6.48(s, 1H), 5.09 (dd, J = 12.9, 5.3 Hz, 1H), 3.83 (s, 6H), 3.73 (s, 2H),3.48 (s, 3H), 3.43-3.35 (m, 2H), 3.07 (s, 6H), 2.95- 2.81 (m, 1H),2.75-2.54 (m, 10H), 2.10-1.97 (m, 1H), 1.40 (s, 6H). D82 752.3 ¹H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.04 (s, 1H), 8.18 (s, 1H, FA), 7.82(d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.36 (dd, J= 8.3, 2.3 Hz, 1H), 6.75 (s, 2H), 6.48 (s, 1H), 5.12 (dd, J = 12.9, 5.4Hz, 1H), 4.24 (dd, J = 10.1, 5.6 Hz, 1H), 4.04 (dd, J = 9.9, 6.1 Hz,1H), 3.80 (s, 6H), 3.54 (s, 3H), 3.48 (s, 4H), 3.07 (s, 6H), 2.99-2.86(m, 2H), 2.63-2.54 (m, 5H), 2.44 (s, 3H), 2.09-2.01 (m, 1H), 1.08 (d, J= 6.6 Hz, 3H). D83 752.25 ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H),9.04 (s, 1H), 8.32 (s, 2H, FA), 7.82 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H),7.47 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 6.74 (s, 2H),6.48 (s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.24 (dd, J = 10.0, 5.5Hz, 1H), 4.04 (dd, J = 10.0, 6.1 Hz, 1H), 3.80 (s, 6H), 3.53 (s, 3H),3.48 (s, 4H), 3.07 (s, 6H), 2.96-2.86 (m, 2H), 2.63-2.54 (m, 5H), 2.42(s, 3H), 2.09-2.00 (m, 1H), 1.07 (d, J = 6.7 Hz, 3H). D84 860.55 ¹H NMR(300 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.72 (s, 1H, HCI), 9.01 (s, 1H),7.86 (dd, J = 8.2, 2.4 Hz, 1H), 7.69-7.62 (m, 1H), 7.36-7.26 (m, 2H),6.93-6.88 (m, 2H), 6.58 (s, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 5.03(q, J = 6.6 Hz, 1H), 4.18 (s, 2H), 3.91 (s, 6H), 3.51 (s, 3H), 3.46-3.23(m, 8H), 3.13 (s, 7H), 3.05 (s, 2H), 2.99-2.84 (m, 3H), 2.65-2.54 (m,4H), 2.31-2.22 (m, 1H), 2.09- 1.81 (m, 11H). D85 461.55 ¹H NMR (400 MHz,DMSO-d6) δ 9.04 (s, 1H), 8.15 (s, 1H, FA), 7.69 (d, J = 8.6 Hz, 1H),7.58 (s, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H),6.78 (s, 2H), 6.49 (s, 1H), 5.71-5.60 (m, 2H), 5.27 (dd, J = 13.1, 5.4Hz, 1H), 4.78 (p, J = 6.2 Hz, 1H), 3.83 (s, 6H), 3.66 (s, 2H), 3.48 (s,3H), 3.43 (t, J = 5.3 Hz, 4H), 3.07 (s, 6H), 3.03-2.79 (m, 4H),2.65-2.55 (m, 3H), 2.40-2.29 (m, 4H), 2.28- 2.04 (m, 3H), 1.66 (d, J =12.1 Hz, 2H), 1.44-1.27 (m, 3H), 1.26- 1.15 (m, 8H). D86 651.44 D87804.4 D88 674.62 ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.01 (s,1H), 8.16 (s, 2H), 7.55 (s, 1H), 6.73 (s, 2H), 6.46 (s, 1H), 3.78 (s,6H), 3.53 (s, 2H), 3.45 (s, 3H), 3.15 (s, 2H), 3.05 (s, 6H), 2.82 (d, J= 11.4 Hz, 2H), 2.40-2.24 (m, 3H), 2.05 (t, J = 11.5 Hz, 2H), 1.80 (dd,J = 9.7, 4.5 Hz, 1H), 1.58 (d, J = 12.3 Hz, 2H), 1.32 (q, J = 7.0 Hz,2H), 1.09 (q, J = 11.6 Hz, 2H). D89 689.53 D90 734.26 D91 720.54 D92706.65 D93 720.4 D94 618.61 ¹H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H),9.01 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 6.73 (s, 2H), 6.44 (s, 1H),4.94 (d, J = 45.9 Hz, 1H), 3.79 (s, 6H), 3.62 (s, 2H), 3.46 (s, 3H),3.36-3.10 (m, 3H), 3.04 (s, 6H), 2.96 (q, J = 4.9, 3.2 Hz, 2H), 2.87(dd, J = 14.8, 7.7 Hz, 3H), 2.84-2.62 (m, 1H), 2.34-2.17 (m, 1H),1.86-1.71 (m, 1H). D95 780.35 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H),9.04 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.40 (dd, J =8.3, 2.3 Hz, 1H), 6.74 (s, 2H), 6.48 (s, 1H), 5.13 (dd, J = 13.0, 5.4Hz, 1H), 4.50 (s, 2H), 4.43 (q, J = 6.1 Hz, 4H), 3.79 (s, 6H), 3.55 (s,2H), 3.47 (s, 3H), 3.07 (s, 6H), 3.04-2.81 (m, 2H), 2.65-2.54 (m, 4H),2.49- 2.39 (m, 5H), 2.10-2.00 (m, 1H). D96 766.4 ¹H NMR (400 MHz,DMSO-d6) δ 11.13 (s, 1H), 9.04 (s, 1H), 8.18 (s, 1H, FA), 7.83 (d, J =8.2 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 8.2,2.2 Hz, 1H), 6.75 (s, 2H), 6.49 (s, 1H), 5.13 (dd, J = 12.9, 5.4 Hz,1H), 3.81 (s, 6H), 3.56 (s, 2H), 3.51- 3.45 (m, 5H), 3.06 (s, 6H),2.94-2.84 (m, 1H), 2.59-2.53 (m, 6H), 2.49-2.43 (m, 4H), 2.08-2.01 (m,1H), 1.35 (s, 6H). D97 831.99 ¹H NMR (400 MHz, Methanol-d4) δ 9.16 (s,1H), 8.46 (s, 1H, FA), 7.64 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 6.91 (s,2H), 6.83 (d, J = 2.1 Hz, 1H), 6.66 (dd, J = 8.3, 2.1 Hz, 1H), 6.48 (s,1H), 5.07 (dd, J = 12.3, 5.4 Hz, 1H), 4.45 (s, 2H), 4.06 (d, J = 9.2 Hz,4H), 3.99 (s, 6H), 3.79 (s, 4H), 3.60 (s, 3H), 3.26-3.19 (m, 1H), 3.13(s, 6H), 2.91-2.81 (m, 1H), 2.80-2.68 (m, 2H), 2.60 (s, 4H), 2.14-2.06(m, 1H), 1.89 (s, 4H), 1.17 (s, 6H). D98 681.35 ¹H NMR (300 MHz,DMSO-d6) δ 11.13 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H, FA), 7.86-7.80 (m,1H), 7.59 (s, 1H), 7.29-7.23 (m, 2H), 6.77 (s, 2H), 6.47 (s, 1H), 5.12(dd, J = 12.9, 5.3 Hz, 1H), 4.95 (t, J = 5.5 Hz, 1H), 3.81 (s, 6H),3.75-3.69 (m, 4H), 3.48 (s, 3H), 3.15- 3.11 (m, 2H), 3.06 (s, 6H),2.91-2.84 (m, 1H), 2.65-2.55 (m, 2H), 2.07-1.99 (m, 1H). D99 914.5 ¹HNMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.04 (s, 1H), 8.30 (s, 1H, FA),7.82 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.34-7.23 (m, 2H), 6.75 (s, 2H),6.49 (s, 1H), 5.12 (dd, J = 12.8, 5.3 Hz, 1H), 5.04- 4.91 (m, 1H), 3.80(s, 6H), 3.52-3.48 (m, 6H), 3.07 (s, 6H), 2.99- 2.67 (m, 8H), 2.44-2.40(m, 2H), 2.08-1.94 (m, 3H), 1.89- 1.75 (m, 3H), 1.64-1.45 (m, 6H),1.35-1.12 (m, 3H). D100 780.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H),9.04 (s, 1H), 7.85 (dd, J = 8.5, 7.3 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H),7.58 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 6.74 (s, 2H), 6.48 (s, 1H), 5.09(dd, J = 12.8, 5.4 Hz, 1H), 4.55 (s, 2H), 4.43 (s, 4H), 3.79 (s, 6H),3.55 (s, 2H), 3.47 (s, 3H), 3.06 (s, 6H), 2.92-2.81 (m, 1H), 2.63-2.54(m, 5H), 2.48- 2.37 (m, 5H), 2.07-1.98 (m, 1H). D101 850.55 ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 9.03 (s, 1H), 8.15 (s, 1H, FA), 7.83 (d,J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.32-7.25 (m, 2H), 7.15 (d, J = 1.6 Hz,1H), 7.11 (d, J = 1.6 Hz, 1H), 6.39 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz,1H), 4.99 (t, J = 6.8 Hz, 1H), 3.85 (s, 3H), 3.60 (s, 2H), 3.47 (s, 3H),3.07 (s, 6H), 2.91-2.80 (m, 3H), 2.64- 2.53 (m, 3H), 2.45-2.40 (m, 2H),2.39-2.36 (m, 1H), 2.30-2.26 (m, 1H), 2.18-2.00 (m, 6H), 1.81 (dd, J =12.3, 6.4 Hz, 2H), 1.68- 1.55 (m, 6H), 1.53-1.46 (m, 1H), 1.10-0.98 (m,2H). D102 864.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.04 (s, 1H),7.84 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.35-7.26 (m, 2H), 7.19 (d, J =13.5 Hz, 2H), 6.40 (s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 5.04 (t, J= 7.3 Hz, 1H), 3.99-3.59 (m, 5H), 3.47 (s, 5H), 3.42-3.35 (m, 4H),3.11-3.03 (m, 7H), 3.02-2.82 (m, 3H), 2.71-2.53 (m, 3H), 2.44-2.34 (m,1H), 2.10-2.00 (m, 1H), 1.93-1.83 (m, 2H), 1.70- 1.45 (m, 8H). D103832.6 ¹H NMR (300 MHz, Methanol-d4) δ 9.09 (s, 1H), 7.72 (d, J = 8.3 Hz,1H), 7.49 (s, 1H), 7.05-6.98 (m, 2H), 6.90 (s, 2H), 6.60-6.55 (m, 1H),5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.95-4.89 (m, 1H), 4.54- 4.37 (m, 4H),3.98 (s, 6H), 3.69-3.49 (m, 7H), 3.42-3.35 (m, 1H), 3.29-3.13 (m, 8H),3.12-2.95 (m, 4H), 2.94-2.86 (m, 1H), 2.84- 2.74 (m, 1H), 2.74-2.63 (m,1H), 2.59-2.44 (m, 2H), 2.37- 2.21 (m, 1H), 2.21-1.97 (m, 9H), 1.73-1.62(m, 1H). D104 693.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.04 (s,1H), 8.17 (s, 1H, FA), 7.88-7.73 (m, 3H), 7.60 (s, 1H), 6.78 (s, 2H),6.50 (s, 1H), 5.14 (dd, J = 12.9, 5.3 Hz, 1H), 3.84 (s, 6H), 3.65 (s,2H), 3.49 (s, 3H), 3.08 (s, 6H), 3.02 (d, J = 11.3 Hz, 2H), 2.97-2.70(m, 3H), 2.63-2.55 (m, 1H), 2.30-2.20 (m, 2H), 2.10-2.00 (m, 1H), 1.83-1.63 (m, 4H). D105 805.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.04(s, 1H), 8.20 (s, 1H, FA), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.30(d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.7, 2.3 Hz, 1H), 6.75 (s, 2H), 6.49(s, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.03 (d, J = 12.9 Hz, 2H),3.80 (s, 6H), 3.54 (s, 2H), 3.48 (s, 3H), 3.07 (s, 6H), 3.01-2.82 (m,4H), 2.64-2.54 (m, 2H), 2.46-2.41 (m, 3H), 2.39-2.24 (m, 6H), 2.07- 1.96(m, 1H), 1.74 (d, J = 12.7 Hz, 2H), 1.64-1.51 (m, 1H), 1.41- 1.30 (m,2H), 1.24-1.08 (m, 2H). D106 791.45 ¹H NMR (300 MHz, DMSO-d6) δ 11.08(s, 1H), 8.97 (s, 1H), 8.16 (s, 1H, FA), 7.65 (d, J = 8.5 Hz, 1H), 7.51(s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.7, 2.3 Hz, 1H), 7.15(d, J = 4.9 Hz, 1H), 6.71 (s, 2H), 6.43 (s, 1H), 5.07 (dd, J = 12.7, 5.3Hz, 1H), 4.04 (d, J = 12.7 Hz, 2H), 3.81 (s, 6H), 3.59 (s, 2H), 3.46 (s,3H), 3.27-3.04 (m, 5H), 2.94 (t, J = 12.6 Hz, 3H), 2.80 (d, J = 4.6 Hz,3H), 2.62- 2.55 (m, 2H), 2.46-2.34 (m, 5H), 2.05-1.96 (m, 1H), 1.74 (d,J = 12.7 Hz, 2H), 1.65-1.51 (m, 1H), 1.44-1.32 (m, 2H), 1.25-1.11 (m,2H). D107 832.75 ¹H NMR (300 MHz, MeOD) δ 9.04 (d, 1H), 7.59-7.45 (m,2H), 7.24- 7.12 (m, 2H), 6.91 (d, 2H), 6.72-6.60 (m, 1H), 5.15 (dd, 1H),4.85- 4.80 (m, 1H), 4.53-4.34 (m, 4H), 3.98 (d, 6H), 3.72-3.65 (m, 2H),3.60-3.47 (m, 4H), 3.43-3.36 (m, 1H), 3.28-3.22 (m, 1H), 3.21-3.13 (m,7H), 3.10 (d, 2H), 3.04-2.95 (m, 1H), 2.94-2.85 (m, 1H), 2.76-2.83 (m,1H), 2.73-2.65 (m, 1H), 2.60-2.43 (m, 2H), 2.35-2.15 (m, 2H), 2.13-2.09(m, 2H), 2.08-2.02 (m , 3H), 2.88-2.78 (m, 3H), 1.52-1.36 (m, 2H). D108874.35 1HNMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.05 (s, 1H), 8.15 (s,0.4H, FA), 7.83 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.32-7.23 (m, 2H),6.85 (s, 2H), 6.50 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.99 (t, J= 6.7 Hz, 1H), 3.96 (s, 2H), 3.87 (s, 6H), 3.49 (s, 3H), 3.27- 3.19 (m,6H), 3.08 (s, 6H), 2.95-2.81 (m, 1H), 2.66-2.53 (m, 2H), 2.45-2.37 (m,4H), 2.10-1.98 (m, 1H), 1.87-1.67 (m, 5H), 1.59 (d, J = 17.9 Hz, 4H),1.49-1.32 (m, 2H), 0.88 (s, 6H). D109 764.25 ¹H NMR (300 MHz, DMSO-d6) δ11.12 (s, 1H), 9.05 (s, 1H), 9.00 (br s, 0.9H, TFA salt), 7.88 (d, J =8.3 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.4,2.3 Hz, 1H), 6.88 (s, 2H), 6.48 (s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz,1H), 4.25 (s, 4H), 3.88 (s, 6H), 3.49 (s, 6H), 3.35 (d, J = 11.0 Hz,3H), 3.08 (s, 6H), 3.06-2.81 (m, 8H), 2.68-2.53 (m, 2H), 2.10-2.00 (m,1H), 0.76 (d, J = 5.9 Hz, 3H). D110 817.45 ¹H NMR (400 MHz, Methanol-d4)δ 9.13 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 6.94-6.85 (m,3H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 6.52 (s, 1H), 5.08 (dd, J = 12.4,5.5 Hz, 1H), 4.53 (s, 2H), 4.40- 4.12 (m, 4H), 3.99 (s, 6H), 3.95-3.78(m, 5H), 3.58 (s, 3H), 3.46- 3.33 (m, 3H), 3.15 (s, 8H), 2.91-2.66 (m,3H), 2.29-2.08 (m, 5H), 1.40 (d, J = 6.7 Hz, 3H). D111 890.4 ¹H NMR (300MHz, DMSO-d6) δ 11.12 (s, 1H), 9.19 (s, 1H, TFA salt), 9.05 (d, J = 1.5Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 11.1 Hz, 1H), 7.35-7.24(m, 2H), 6.91 (d, J = 4.1 Hz, 2H), 6.51 (d, J = 12.2 Hz, 1H), 5.18-4.99(m, 2H), 4.25 (s, 1H), 3.91 (d, J = 1.3 Hz, 6H), 3.81 (s, 1H), 3.57-3.33(m, 9H), 3.30 (s, 3H), 3.23-3.01 (m, 8H), 2.99-2.81 (m, 2H), 2.66-2.53(m, 2H), 2.53-2.39 (m, 2H), 2.40-2.30 (m, 1H), 2.11-2.00 (m, 1H), 1.89(s, 2H), 1.67- 1.45 (m, 5H). D112 844.55 ¹H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 9.04 (s, 1H), 8.15 (s, 1H, FA), 7.83 (d, J = 8.2 Hz, 1H),7.55 (s, 1H), 7.38-7.22 (m, 2H), 6.96 (d, J = 10.0 Hz, 2H), 6.45 (s,1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.06-4.93 (m, 1H), 3.82 (s, 3H),3.65 (s, 2H), 3.48 (s, 3H), 3.07 (s, 6H), 2.95-2.81 (m, 3H), 2.82-2.72(m, 2H), 2.70- 2.53 (m, 3H), 2.49-2.38 (m, 4H), 2.38-2.13 (m, 5H),2.11-1.98 (m, 1H), 1.84 (dd, J = 11.9, 6.4 Hz, 2H), 1.77-1.41 (m, 7H),1.22 (t, J = 7.5 Hz, 3H), 1.18- 0.98 (m, 2H). D113 680.2 ¹H NMR (300MHz, DMSO-d6) δ 10.97 (s, 1H), 9.04 (s, 1H), 7.60 (s, 1H), 7.42 (d, J =8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.3 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H),6.79 (s, 2H), 6.50 (s, 1H), 5.09 (dd, J = 13.2, 5.0 Hz, 1H), 4.41-4.14(m, 2H), 3.84 (s, 6H), 3.67 (s, 2H), 3.48 (s, 3H), 3.19 (s, 4H), 3.08(s, 6H), 2.91 (ddd, J = 17.9, 13.6, 5.5 Hz, 1H), 2.65 (s, 4H), 2.48-2.24(m, 2H), 2.06-1.92 (m, 1H). D114 680.3 ¹H NMR (300 MHz, DMSO-d6) δ 10.94(s, 1H), 9.04 (s, 1H), 7.60 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.05 (d,J = 7.9 Hz, 2H), 6.79 (s, 2H), 6.50 (s, 1H), 5.05 (dd, J = 13.3, 5.1 Hz,1H), 4.40-4.10 (m, 2H), 3.84 (s, 6H), 3.65 (s, 2H), 3.48 (s, 3H),3.33-3.20 (m, 4H), 3.08 (s, 6H), 2.96-2.83 (m, 1H), 2.59 (d, J = 14.6Hz, 4H), 2.45- 2.25 (m, 2H), 1.95 (dd, J = 12.1, 6.5 Hz, 1H). D115 833.8¹H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.02 (s, 1H), 8.16 (s, 1H,FA), 7.65 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 7.30 (d, J = 2.1 Hz, 1H),7.23 (dd, J = 8.9, 2.1 Hz, 1H), 6.74 (s, 2H), 6.40 (s, 1H), 5.06 (dd, J= 12.7, 5.3 Hz, 1H), 4.03 (d, J = 13.0 Hz, 2H), 3.80 (s, 6H), 3.57 (s,2H), 3.55-3.44 (m, 7H), 3.03-2.71 (m, 4H), 2.64- 2.53 (m, 2H), 2.48-2.25(m, 9H), 2.07-1.94 (m, 1H), 1.79-1.51 (m, 3H), 1.42-1.31 (m, 2H),1.26-1.04 (m, 8H). D116 815.35 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s,1H), 9.02 (s, 1H), 8.17 (s, 1H, FA), 7.64 (d, J = 8.3 Hz, 1H), 7.60 (s,1H), 6.78 (s, 3H), 6.66- 6.53 (m, 1H), 6.18 (s, 1H), 5.05 (dd, J = 12.9,5.4 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.89 (s, 2H), 3.85 (s, 6H), 3.74(s, 4H), 3.49 (s, 3H), 3.30-3.17 (m, 4H), 2.95-2.80 (m, 1H), 2.58-2.54(m, 2H), 2.49- 2.43 (m, 3H), 2.40-2.23 (m, 6H), 2.07-1.96 (m, 1H), 1.78-1.70 (m, 4H). D117 688.91 ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H),9.01 (s, 1H), 8.23 (s, 2H), 7.55 (s, 1H), 6.72 (s, 2H), 6.46 (s, 1H),3.78 (s, 6H), 3.49 (s, 2H), 3.45 (s, 3H), 3.05 (s, 6H), 2.85-2.74 (m,2H), 2.69-2.60 (m, 1H), 2.35-2.20 (m, 3H), 1.99 (t, J = 11.3 Hz, 2H),1.85-1.74 (m, 1H), 1.56 (d, J = 12.0 Hz, 2H), 1.40 (s, 2H), 1.15 (s,4H), 1.04 (d, J = 11.3 Hz, 2H). D118 878.25 ¹H NMR (300 MHz, DMSO-d6) δ9.04 (s, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 4.1 Hz, 1H), 7.51(t, J = 6.9 Hz, 1H), 6.89 (s, 2H), 6.51 (d, J = 7.4 Hz, 1H), 5.18-5.06(m, 2H), 4.21 (s, 2H), 3.90 (d, J = 1.7 Hz, 6H), 3.50 (s, 4H), 3.41-3.29(m, 3H), 3.32-3.18 (m, 1H), 3.09 (s, 7H), 3.00-2.79 (m, 2H), 2.78-2.53(m, 6H), 2.10- 2.00 (m, 1H), 1.95-1.75 (m, 6H), 1.72-1.42 (m, 4H). D119854.45 ¹H NMR (400 MHz, Methanol-d4) δ 9.20-8.98 (m, 1H), 7.83 (d, J =8.3 Hz, 1H), 7.78 (s, 2H), 7.50 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.26(dd, J = 8.3, 2.3 Hz, 1H), 6.37 (s, 1H), 5.12 (dd, J = 12.5, 5.4 Hz,1H), 4.99 (t, J = 6.6 Hz, 1H), 4.75 (s, 2H), 3.88-3.75 (m, 2H), 3.68-3.51 (m, 5H), 3.44 (t, J = 12.4 Hz, 2H), 3.15 (s, 8H), 3.11-2.92 (m,2H), 2.91-2.83 (m, 1H), 2.81-2.67 (m, 3H), 2.61-2.53 (m, 1H), 2.40-2.25(m, 1H), 2.15 (d, J = 14.4 Hz, 6H), 2.02 (s, 3H), 1.78 (s, 2H). D120791.3 ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.04 (s, 1H), 8.16 (s,1H, FA), 7.58 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.31-7.11 (m, 2H), 6.76(s, 2H), 6.49 (s, 1H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H), 4.41- 4.11 (m,2H), 3.81 (s, 6H), 3.73 (d, J = 12.0 Hz, 2H), 3.57 (s, 2H), 3.48 (s,3H), 3.07 (s, 6H), 2.98-2.81 (m, 1H), 2.80-2.59 (m, 3H), 2.58-2.57 (m,1H), 2.46-2.43 (m, 3H), 2.43-2.22 (m, 7H), 2.06- 1.92 (m, 1H), 1.83-1.67(m, 2H), 1.46-1.34 (m, 3H), 1.33- 1.17 (m, 2H). D121 791.3 ¹H NMR (300MHz, DMSO-d6) δ 10.93 (s, 1H), 9.04 (s, 1H), 8.14 (s, 1H, FA), 7.64-7.42(m, 2H), 7.04 (d, J = 7.4 Hz, 2H), 6.78 (s, 2H), 6.49 (s, 1H), 5.04 (dd,J = 13.2, 5.1 Hz, 1H), 4.42-4.14 (m, 2H), 3.88 (s, 1H), 3.82 (s, 7H),3.65 (s, 2H), 3.48 (s, 4H), 3.07 (s, 6H), 3.00-2.69 (m, 4H), 2.69-2.54(m, 7H), 2.48-2.24 (m, 3H), 2.04-1.88 (m, 1H), 1.74 (d, J = 11.8 Hz,2H), 1.47 (d, J = 26.5 Hz, 3H), 1.21 (q, J = 11.7, 10.6 Hz, 2H). D122801.5 ¹H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 7.66 (d, J = 8.4 Hz,1H), 7.37 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.86 (s, 2H), 6.16 (s, 1H),5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49-4.35 (m, 4H), 4.08 (t, J = 7.4 Hz,4H), 3.98 (s, 6H), 3.60 (d, J = 12.3 Hz, 2H), 3.41 (t, J = 4.9 Hz, 4H),3.31-3.27 (m, 1H), 3.19 (t, J = 12.4 Hz, 2H), 2.99-2.85 (m, 1H),2.83-2.74 (m, 5H), 2.70-2.61 (m, 1H), 2.56-2.39 (m, 3H), 2.22-2.13 (m,3H), 1.93 (s, 2H), 1.14 (q, J = 6.8 Hz, 2H), 0.96 (dd, J = 6.3, 4.1 Hz,2H). D123 789.5 ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.38 (br s,1H, TFA salt), 9.04 (s, 1H), 7.65-7.57 (m, 2H), 7.21-7.12 (m, 2H), 6.90(s, 2H), 6.22 (s, 1H), 5.07 (dd, J = 12.9, 5.0 Hz, 1H), 4.37 (d, J =16.9 Hz, 1H), 4.30-4.20 (m, 2H), 4.01 (q, J = 7.3 Hz, 7H), 3.93 (s, 7H),3.66-3.56 (m, 2H), 3.26-3.04 (m, 7H), 2.95-2.85 (m, 2H), 2.80- 2.54 (m,3H), 2.41-2.23 (m, 4H), 2.05-1.91 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H).D124 819.65 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.04 (s, 1H),7.67 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.33 (s, J = 2.3 Hz, 1H), 7.25(d, J = 8.7, 2.3 Hz, 1H), 6.89 (s, 2H), 6.48 (s, 1H), 5.07 (dd, J =12.9, 5.4 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 3.88 (s, 6H), 3.62-3.26(m, J = 7.0 Hz, 12H), 3.10 (s, 3H), 3.03-2.83 (m, 8H), 2.64-2.53 (m,2H), 2.07-1.98 (m, 1H), 1.76 (d, J = 12.7 Hz, 2H), 1.58 (s, 3H), 1.29-1.15 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H). D125 831.25 ¹H NMR (400 MHz,DMSO-d6): δ 11.06 (s, 1H), 9.04 (s, 1H), 8.16 (s, 2H), 7.63 (d, J = 8.4Hz, 1H), 7.58 (s, 1H), 6.77 (s, 3H), 6.64 (dd, J = 8, 2 Hz, 1H), 6.49(s, 1H), 5.05 (dd, J = 13.2, 5.2 Hz, 1H), 3.81 (s, 6H), 3.74 (s, 4H),3.64 (s, 2H), 3.48 (s, 3H), 3.07 (s, 6H), 2.94- 2.80 (m, 3H), 2.60-2.52(m, 4H), 2.30-2.12 (m, 4H), 2.08 (d, J = 6.8 Hz, 2H), 2.05-1.93 (m, 1H),1.75 (s, 3H), 1.65 (d, J = 12.8 Hz, 2H), 1.55-1.45 (m, 1H), 1.24 (s,0.2H), 1.19-1.01 (m, 2H). D126 746.2 ¹H NMR (400 MHz, Methanol-d4) δ8.99-8.94 (m, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 6.88 (s, 2H),6.87 (d, J = 2.0 Hz, 1H), 6.75- 6.68 (m, 1H), 6.38 (d, J = 1.8 Hz, 1H),5.12-5.02 (m, 1H), 4.44 (s, 2H), 4.23 (t, J = 7.6 Hz, 4H), 3.99 (s, 8H),3.87 (s, 2H), 3.60 (s, 4H), 3.34 (s, 1H), 3.31-3.19 (m, 2H), 2.95-2.81(m, 1H), 2.81- 2.64 (m, 2H), 2.60-2.48 (m, 2H), 2.30 (d, J = 14.4 Hz,2H), 2.21- 2.07 (m, 3H). D127 720.45 ¹H NMR (400 MHz, DMSO-d6) δ 10.90(s, 1H), 9.01 (s, 1H), 8.17 (s, 1H), 7.51 (d, J = 37.4 Hz, 1H), 6.74 (s,2H), 6.65-6.35 (m, 3H), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-3.99 (m,2H), 3.80 (s, 5H), 3.59 (s, 3H), 3.54 (s, 2H), 3.46 (s, 2H), 3.15 (s,1H), 3.05 (s, 5H), 2.58 (s, 1H), 2.45-2.39 (m, 5H), 2.39-2.27 (m, 1H),1.93 (ddq, J = 10.4, 5.4, 3.2, 2.6 Hz, 1H), 1.71 (t, J = 5.4 Hz, 4H).D128 720.52 ¹H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.02 (s, 1H),8.12 (s, 1H), 7.57 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.80 (s, 2H), 6.67(d, J = 7.5 Hz, 2H), 6.47 (s, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H),4.37- 4.07 (m, 2H), 3.84 (s, 7H), 3.60 (s, 4H), 3.47 (s, 3H), 3.06 (s,6H), 2.97-2.84 (m, 1H), 2.81 (d, J = 25.0 Hz, 0H), 2.69-2.52 (m, 1H),2.42-2.26 (m, 1H), 2.05-1.92 (m, 1H), 1.85 (s, 4H). D129 864.3 ¹H NMR(400 MHz, Methanol-d4) δ 9.02 (s, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.58(s, 1H), 7.45 (d, J = 6.7, 3.2 Hz, 1H), 6.91 (d, J = 4.3 Hz, 2H), 6.70(d, J = 9.3 Hz, 1H), 5.17-5.03 (m, 2H), 4.41 (s, 2H), 3.98 (d, J = 4.1Hz, 6H), 3.65 (d, J = 12.7 Hz, 2H), 3.60 (s, 3H), 3.54 (d, J = 15.9 Hz,1H), 3.38 (s, 1H), 3.21 (s, 6H), 3.19-3.18 (m, 1H), 3.16- 2.95 (m, 4H),2.92-2.82 (m, 1H), 2.82-2.65 (m, 3H), 2.58 (s, 1H), 2.27 (s, 1H),2.22-2.07 (m, 6H), 2.07-1.93 (m, 4H), 1.66 (q, J = 12.3 Hz, 2H). D130876.5 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.29 (s, 1H, TFA salt),9.11 (s, 1H, TFA salt), 9.06 (s, 1H), 7.86 (dd, J = 8.2, 2.7 Hz, 1H),7.63-7.55 (m, 1H), 7.37-7.24 (m, 2H), 6.96-6.87 (m, 2H), 6.56-6.46 (m,1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.02 (t, J = 6.7 Hz, 1H),4.38-4.21 (m, 2H), 3.91 (s, 6H), 3.50 (s, 3H), 3.43 (d, J = 2.2 Hz, 1H),3.39 (s, 3H), 3.36-3.30 (m, 1H), 3.28-3.12 (m, 2H), 3.09 (s, 6H),3.04-2.80 (m, 6H), 2.70-2.54 (m, 3H), 2.47-2.38 (m, 1H), 2.31-2.18 (m,1H), 2.13-1.93(m, 4H), 1.94-1.69 (m, 7H). D131 775.2 ¹H NMR (400 MHz,Methanol-d4) δ 8.97 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.59(s, 1H), 7.20 (d, J = 6.5 Hz, 2H), 6.88 (s, 2H), 6.39 (s, 1H), 5.14 (dd,J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 7.1 Hz, 4H), 4.23 (t, J = 7.6 Hz,4H), 3.98 (s, 6H), 3.86-3.63 (m, 6H), 3.60 (s, 4H), 3.58-3.46 (m, 3H),3.31-3.24 (m, 3H), 2.99-2.86 (m, 1H), 2.84-2.75 (m, 1H), 2.60-2.42 (m,5H), 2.18 (d, J = 16.2 Hz, 3H). D132 665.55 ¹H NMR (400 MHz,Methanol-d4) δ 8.97 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.59(s, 1H), 7.20 (d, J = 6.5 Hz, 2H), 6.88 (s, 2H), 6.39 (s, 1H), 5.14 (dd,J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 7.1 Hz, 4H), 4.23 (t, J = 7.6 Hz,4H), 3.98 (s, 6H), 3.86-3.63 (m, 6H), 3.60 (s, 4H), 3.58-3.46 (m, 3H),3.31-3.24 (m, 3H), 2.99-2.86 (m, 1H), 2.84-2.75 (m, 1H), 2.60-2.42 (m,5H), 2.18 (d, J = 16.2 Hz, 3H). D133 693.35 ¹H NMR (400 MHz, DMSO-d6) δ11.09 (s, 1H), 9.04 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 2.7Hz, 1H), 7.14 (d, J = 7.2 Hz, 2H), 6.76 (s, 2H), 6.49 (s, 1H), 5.06 (dd,J = 12.9, 5.4 Hz, 1H), 3.97 (d, J = 13.3 Hz, 1H), 3.82 (s, 6H), 3.76 (d,J = 13.1 Hz, 1H), 3.48 (s, 3H), 3.06 (s, 7H), 2.95-2.82 (m, 2H),2.71-2.54 (m, 4H), 2.01 (d, J = 12.7 Hz, 1H), 1.85 (s, 1H), 1.72 (d, J =11.2 Hz, 2H), 1.35 (tt, J = 33.0, 18.0 Hz, 2H). D134 831.6 ¹H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 8.15 (s, 0.18H, FA),7.66(d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 7.27-7.20 (m, 1H), 6.79(s, 2H), 6.50 (s, 1H), 6.06-5.96 (m, 1H), 5.23-5.13 (m, 2H), 5.07 (dd, J= 13.0, 5.4 Hz, 1H), 4.57 (d, J = 5.5 Hz, 2H), 4.05 (d, J = 12.9 Hz,2H), 3.83 (s, 6H), 3.62 (s, 1H), 3.39 (s, 3H), 3.08 (s, 6H), 3.03-2.75(m, 7H), 2.59 (dd, J = 12.6, 2.9 Hz, 3H), 2.56 (d, J = 2.0 Hz, 3H),2.08-1.98 (m, 1H), 1.75 (d, J = 12.8 Hz, 2H), 1.64-1.45 (m, 3H),1.26-1.13 (m, 2H). D135 845.5 ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H),9.04 (s, 1H), 8.15 (s, 0.48H, FA), 7.65 (d, J = 8.5 Hz, 1H), 7.55 (s,1H), 7.34-7.20 (m, 2H), 6.77 (s, 2H), 6.51 (s, 1H), 5.95-5.76 (m, 1H),5.14-4.99 (m, 3H), 4.09-3.96 (m, 4H), 3.82 (s, 6H), 3.64 (s, 2H), 3.07(s, 6H), 2.99-2.86 (m, 3H), 2.65-2.52 (m, 8H), 2.49-2.40 (m, 6H), 2.08-1.94 (m, 1H), 1.74 (d, J = 12.7 Hz, 2H), 1.58 (s, 1H), 1.45-1.34 (m,2H), 1.27-1.08 (m, 2H). D136 843.5 ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s,1H), 9.42 (s, 2H, TFA salt), 9.03 (s, 1H), 7.73-7.58 (m, 2H), 6.91-6.62(m, 4H), 6.22 (d, J = 5.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H),4.40-4.19 (m, 2H), 4.03 (t, J = 7.4 Hz, 4H), 3.91 (s, 8H), 3.84 (d, J =5.0 Hz, 2H), 3.22 (s, 3H), 3.12-2.81 (m, 7H), 2.62 (s, 1H), 2.59-2.53(m, 4H), 2.34 (q, J = 7.5 Hz, 2H), 2.20-2.15 (m, 3H), 2.08-1.85 (m, 6H),1.52- 1.46(m, 2H). D137 693.1 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),9.01 (s, 1H), 7.88- 7.79 (m, 1H), 7.60 (s, 1H), 7.27 (d, 2H), 6.74 (s,2H), 6.18 (s, 1H), 5.12-4.96 (m, 2H), 3.99 (t, 4H), 3.82 (s, 6H),3.78-3.70 (m, 3H), 3.48 (s, 4H), 3.24-3.13 (m, 2H), 2.97-2.80 (m, 1H),2.66- 2.62 (m, 1H), 2.61-2.54 (m, 1H), 2.30-2.28 (m, 2H), 2.10-1.92 (m,1H). D138 669.15 ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.04 (s,1H), 8.16 (s, 1H, FA), 7.82 (dd, J = 7.5, 0.9 Hz, 1H), 7.59 (s, 1H),6.76 (s, 2H), 6.46 (s, 1H), 6.38-6.30 (m, 2H), 5.29 (dd, J = 12.5, 5.2Hz, 1H), 4.76 (t, J = 5.6 Hz, 1H), 3.81 (s, 6H), 3.76-3.63 (m, 4H), 3.48(s, 3H), 3.10 (dd, J = 8.2, 4.8 Hz, 2H), 3.06 (s, 6H), 2.97-2.83 (m,1H), 2.68-2.59 (m, 1H), 2.48-2.37 (m, 1H), 2.27-2.07 (m, 1H). D139 831.8¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.05 (s, 1H), 8.15 (s, 1H,FA), 7.67-7.62 (m, 2H), 7.33-7.21 (m, 3H), 6.79 (s, 2H), 6.47 (s, 1H),6.06 (dd, J = 14.3, 6.8 Hz, 1H), 5.06 (dd, J = 12.9, 5.2 Hz, 1H), 4.03(d, J = 12.8 Hz, 2H), 3.81 (s, 6H), 3.56 (s, 2H), 3.31 (s, 4H), 3.08 (s,6H), 2.94-2.90 (m, 3H), 2.63-2.58 (m, 3H), 2.46- 2.37 (m, 4H), 2.02 (s,2H), 1.82 (dd, J = 6.7, 1.7 Hz, 3H), 1.74 (d, J = 12.8 Hz, 2H), 1.58 (s,1H), 1.38-1.36 (m, 2H), 1.17-1.17 (m, 2H). D140 848.45 ¹H NMR (300 MHz,DMSO-d6) δ 11.13 (s, 1H), 9.03 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.60(s, 1H), 7.40-7.23 (m, 4H), 6.34 (s, 1H), 5.12 (dd, J = 12.9, 5.3 Hz,1H), 5.04-4.94 (m, 1H), 3.65 (s, 2H), 3.47 (s, 3H), 3.06 (s, 6H), 2.89(s, 1H) 2.86-2.76 (m, 4H), 2.63 (s, 5H), 2.13 (d, J = 11.0 Hz, 3H), 2.07(s, 1H), 1.82 (dd, J = 11.9, 6.4 Hz, 4H), 1.68 (s, 2H), 1.63 (s, 7H),1.24 (t, J = 7.4 Hz, 3H), 1.03 (d, J = 11.9 Hz, 2H). D141 736.35 ¹H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.52 (s, 1H, TFA), 9.09 (s, 1H),7.78 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.35(dd, J = 8.6, 2.3 Hz, 1H), 6.90 (s, 2H), 6.67 (s, 1H), 5.10 (dd, J =13.0, 5.3 Hz, 1H), 4.42-4.31 (m, 2H), 4.20 (d, J = 12.6 Hz, 2H), 3.92(s, 6H), 3.70 (t, J = 4.8 Hz, 5H), 3.63-3.55 (m, 8H), 3.32 (h, J = 11.6,10.4 Hz, 4H), 2.90 (ddd, J = 17.4, 14.0, 5.4 Hz, 1H), 2.65-2.54 (m, 2H),2.07-2.00 (m, 1H). D142 732.5 ¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H),9.02 (s, 1H), 8.24 (s, 1H, FA), 7.61 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H),6.78-6.63 (m, 4H), 6.21 (s, 1H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H),4.35-4.15 (m, 2H), 4.01 (t, J = 7.3 Hz, 4H), 3.82 (s, 6H), 3.58-3.48 (m,8H), 2.97- 2.85 (m, 1H), 2.67-2.55 (m, 2H), 2.42-2.26 (m, 7H), 1.98 (d,J = 12.6 Hz, 1H), 1.80-1.62 (m, 4H). D143 789.55 ¹H NMR (300 MHz,DMSO-d6) δ 10.96 (s, 1H), 9.85 (br s, 2H, TFA salt), 9.05 (s, 1H), 7.59(s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 3.5 Hz, 2H), 6.56-6.44(m, 3H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.42 (d, J = 5.4 Hz, 1H), 4.37(s, 1H), 4.35 (s, 1H), 4.29 (s, 2H), 4.25 (s, 1H), 4.05 (t, J = 8.8 Hz,2H), 3.91 (s, 6H), 3.78 (s, 2H), 3.70 (s, 2H), 3.50 (s, 3H), 3.41 (d, J= 17.2 Hz, 4H), 3.17 (s, 1H), 3.09 (s, 6H), 3.00-2.84 (m, 3H), 2.59 (d,J = 15.0 Hz, 1H), 2.35 (dd, J = 13.0, 4.5 Hz, 1H), 2.13 (d, J = 13.8 Hz,2H), 2.03-1.83 (m, 3H). D144 711.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s,1H), 9.07 (s, 1H), 8.19 (s, 0.6H, FA), 7.87-7.78 (m, 1H), 7.63 (s, 1H),6.74 (s, 2H), 6.63 (s, 1H), 6.40-6.29 (m, 2H), 5.29 (dd, J = 12.5, 5.2Hz, 1H), 4.76 (t, J = 5.5 Hz, 1H), 3.81 (s, 6H), 3.68-3.57 (m, 8H),3.52-3.50 (m, 7H), 3.10 (t, J = 6.4 Hz, 2H), 2.99-2.81 (m, 1H),2.66-2.50 (m, 1H), 2.49-2.38 (m, 1H), 2.16-2.08 (m, 1H). D145 805.25 ¹HNMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.01 (s, 1H), 7.67 (d, J = 8.5Hz, 1H), 7.37 (d, J = 25.2 Hz, 2H), 7.25 (d, 1H), 7.20- 7.04 (m, 1H),6.99 (s, 1H), 5.92 (s, 1H), 5.10-4.99 (m, 1H), 4.08 (d, J = 13.2 Hz,3H), 3.79 (s, 4H), 3.69 (s, 5H), 3.46 (s, 4H), 3.13 (s, 5H), 3.01 (s,7H), 2.96-2.79 (m, 4H), 2.74-2.55 (m, 2H), 2.06- 1.92 (m, 1H), 1.76 (d,2H), 1.60 (s, 3H), 1.31-1.19 (m, 2H). D146 677.35 ¹H NMR (400 MHz,DMSO-d6) δ 11.14 (s, 1H), 9.01 (s, 1H), 8.18 (s, 1H, FA), 7.90-7.82 (m,2H), 7.81-7.74 (m, 1H), 7.62 (s, 1H), 6.75 (s, 2H), 6.19 (s, 1H), 5.15(dd, J = 12.8, 5.4 Hz, 1H), 3.99 (t, J = 7.4 Hz, 4H), 3.83 (s, 6H),3.79-3.60 (m, 6H), 3.48 (s, 3H), 3.26 (s, 1H), 2.98-2.80 (m, 1H),2.66-2.52 (m, 2H), 2.33 (m, J = 7.2 Hz, 2H), 2.10-2.01 (m, 1H). D147831.4 ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.05 (s, 1H), 8.14 (s,0.4H, FA), 7.47 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.02(s, 1H), 6.74-6.65 (m, 2H), 6.05 (s, 1H), 5.08 (dd, J = 13.2, 5.0 Hz,1H), 4.40-4.14 (m, 4H), 4.16-4.06 (m, 2H), , 3.82 (s, 3H), 3.70-3.51 (m,8H), 3.63 (s, 3H), 3.51-3.48 (m, 8H), 3.43-3.34 (m, 4H), 3.11-2.70 (m,1H), 2.76-2.57 (m, 4H), , 2.41-2.27 (m, 2H), ), 2.03-1.93 (m, 1H),1.98-1.85 (m, 4H). D148 702.46 D149 702.46 ¹H NMR (400 MHz, DMSO-d6) δ10.92 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 7.59-7.46 (m, 1H), 7.37 (dd,J = 18.7, 7.8 Hz, 2H), 7.17- 6.87 (m, 2H), 6.67 (d, J = 8.1 Hz, 2H),5.05 (dd, J = 13.3, 5.2 Hz, 1H), 4.39-4.05 (m, 2H), 4.07-3.89 (m, 5H),3.82 (d, J = 7.8 Hz, 4H), 3.58 (s, 3H), 3.47 (d, J = 16.6 Hz, 5H),2.97-2.79 (m, 1H), 2.67-2.51 (m, 2H), 2.45-2.26 (m, 9H), 2.08-1.88 (m,2H), 1.77 (d, J = 5.4 Hz, 5H). D150 773.42 D151 845.25 ¹H NMR (400 MHz,Methanol-d4) δ 9.10 (d, J = 0.7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.40(d, J = 4.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 2.4Hz, 1H), 6.87 (d, J = 1.3 Hz, 2H), 6.57 (s, 1H), 5.87-5.76 (m, 1H),5.73-5.51 (m, 1H), 5.08 (dd, J = 12.5, 5.4 Hz, 1H), 4.75-4.69 (m, 1H),4.57 (d, J = 6.2 Hz, 2H), 4.35 (s, 2H), 4.07 (d, J = 13.2 Hz, 2H), 3.96(s, 6H), 3.47-3.35 (m, 4H), 3.30-3.19 (m, 3H), 3.16 (s, 6H), 3.07-2.94(m, 4H), 2.92-2.81 (m, 1H), 2.82- 2.65 (m, 2H), 2.17-2.06 (m, 1H),1.93-1.81 (m, 3H), 1.73 (dd, J = 6.4, 1.4 Hz, 3H), 1.71-1.60 (m, 2H),1.44-1.31 (m, 2H). D152 789.4 ¹H NMR (300 MHz, Methanol-d4) δ 9.12 (s,1H), 7.50-7.39 (m, 2H), 6.89 (d, J = 2.7 Hz, 3H), 6.81 (dd, J = 8.2, 2.2Hz, 1H), 6.52 (s, 1H), 5.17-5.11 (m, 1H), 4.57-4.52 (m, 2H), 4.40 (d, J= 6.5 Hz, 4H), 4.18 (s, 2H), 3.97 (s, 6H), 3.78 (s, 4H), 3.67 (s, 1H),3.60 (s, 4H), 3.57-3.50 (m, 4H), 3.15 (s, 8H), 2.98-2.80 (m, 2H), 2.60-2.44 (m, 1H), 2.32-2.01 (m, 5H). D153 801.6 ¹H NMR (300 MHz, DMSO-d6) δ10.95 (s, 1H), 9.02 (s, 1H), 8.22 (s, 2H, FA), 7.60 (s, 1H), 7.48 (d, J= 8.2 Hz, 1H), 6.76 (s, 2H), 6.54- 6.42 (m, 2H), 6.19 (s, 1H), 5.04 (dd,J = 13.2, 5.1 Hz, 1H), 4.30 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 17.0 Hz,1H), 4.01 (t, J = 7.4 Hz, 4H), 3.83 (s, 6H), 3.78 (s, 2H), 3.62 (s, 3H),3.59-3.52 (m, 2H), 3.48 (s, 3H), 3.13 (s, 2H), 2.91 (ddd, J = 17.8,13.5, 5.4 Hz, 1H), 2.64-2.57 (m, 2H), 2.56-2.49 (m, 3H), 2.44 (d, J =6.9 Hz, 2H), 2.40-2.24 (m, 5H), 2.00-1.88 (m, 1H), 1.73 (t, J = 5.4 Hz,4H). D154 682.5 ¹H NMR (300 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.43 (s, 1H), 6.81 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H),6.52 (s, 1H), 6.14 (s, 1H), 5.26 (d, J = 10.2 Hz, 1H), 3.92 (s, 8H),3.59 (s, 3H), 3.42 (s, 4H), 3.12 (s, 6H), 3.0-2.80 (m, 6H), 2.70-2.52(m, 1H), 2.40-2.20 (m, 1H). D155 791.45 ¹H NMR (300 MHz, Methanol-d4) δ9.16 (d, J = 0.7 Hz, 1H), 8.53 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.44(s, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.7, 2.4 Hz, 1H), 6.86(s, 2H), 6.51 (s, 1H), 5.08 (dd, J = 12.3, 5.4 Hz, 1H), 4.21 (s, 2H),4.06 (d, J = 13.0 Hz, 2H), 3.95 (s, 6H), 3.60 (s, 3H), 3.24-3.10 (m,10H), 3.10-2.96 (m, 3H), 2.95- 2.77 (m, 3H), 2.76-2.62 (m, 3H), 2.36 (d,J = 6.6 Hz, 2H), 2.17- 2.06 (m, 1H), 1.98-1.86 (m, 3H), 1.39-1.22 (m,2H). D156 859.55 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.28 (s,1H), 7.85 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J =11.1 Hz, 2H), 6.81 (s, 2H), 5.12-5.01 (m, 1H), 4.06 (d, J = 12.9 Hz,2H), 3.83 (s, 6H), 3.71-3.43 (m, 5H), 3.17-2.70 (m, 9H), 2.66-2.52 (m,4H), 2.52-2.13 (m, 5H), 2.06-2.00 (m, 1H), 1.75 (d, J = 12.3 Hz, 2H),1.59-1.53 (m, 3H), 1.24-1.14 (m, 2H). D157 682.1 ¹H NMR (400 MHz, DMSO)δ 11.13 (s, 1H), 9.03 (s, 1H), 7.89- 7.83 (m, 1H), 7.56 (s, 1H), 7.29(d, J = 7.5 Hz, 2H), 6.81 (s, 2H), 6.47 (s, 1H), 5.28-5.18 (m, 1H), 5.13(dd, J = 12.9, 5.4 Hz, 1H), 4.88 (tt, J = 7.1, 7.1, 3.9, 3.9 Hz, 1H),3.85 (s, 6H), 3.47 (s, 3H), 3.07 (s, 6H), 2.90 (ddd, J = 18.9, 13.7, 5.3Hz, 1H), 2.69 (ddd, J = 13.4, 6.3, 3.3 Hz, 2H), 2.64-2.51 (m, 2H), 2.40(ddd, J = 12.3, 6.7, 4.2 Hz, 2H), 2.11-2.00 (m, 1H). D158 805.4 ¹H NMR(300 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.20-9.86 (m, 1H), 9.30-9.10 (m,1H), 9.02 (s, 1H), 7.84 (dd, J = 7.8, 4.2 Hz, 1H), 7.63 (d, J = 2.1 Hz,1H), 6.87 (s, 2H), 6.80-6.68 (m, 1H), 6.35 (d, J = 5.7 Hz, 1H), 6.23 (d,J = 5.7 Hz, 1H), 5.27 (dd, J = 12.3, 5.1 Hz, 1H), 4.22 (d, J = 3.6 Hz,2H), 4.10-3.96 (m, 6H), 3.90 (s, 6H), 3.65- 3.52 (m, 2H), 3.50-3.34 (m,5H), 3.30-3.10 (m, 6H), 3.08-2.80 (m, 2H), 2.75-2.60 (m, 1H), 2.50-2.42(m, 2H), 2.42-2.28 (m, 2H), 2.20-2.08 (m, 1H), 1.96-1.70 (m, 3H),1.70-1.40 (m, 4H). D159 843.45 ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s,1H), 9.02 (s, 1H), 7.62- 7.40 (m, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.75(s, 2H), 6.20 (s, 1H), 5.86-5.53 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz,1H), 4.54 (dd, J = 34.6, 6.2 Hz, 2H), 4.38-4.14 (m, 2H), 4.01 (t, J =7.4 Hz, 4H), 3.82 (s, 8H), 3.67 (s, 2H), 3.00-2.71 (m, 5H), 2.61 (s,9H), 2.35 (d, J = 8.0 Hz, 3H), 1.95 (d, J = 11.4 Hz, 1H), 1.80-1.59 (m,5H), 1.45 (s, 3H), 1.21 (d, J = 13.5 Hz, 2H). D160 772.2 ¹H NMR (300MHz, DMSO-d6) δ 10.95 (s, 1H), 9.02 (s, 1H), 8.15 (s, 1H), 7.59-7.44 (m,2H), 6.76 (s, 2H), 6.55-6.44 (m, 2H), 6.20 (s, 1H), 5.66 (qq, J = 10.0,5.4, 5.0 Hz, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.55 (dd, J = 34.7,6.0 Hz, 2H), 4.34-4.13 (m, 2H), 4.01 (t, J = 7.4 Hz, 4H), 3.84 (s, 6H),3.68 (d, J = 16.8 Hz, 6H), 2.97- 2.84 (m, 1H), 2.61 (s, 5H), 2.39-2.29(m, 3H), 1.94 (dd, J = 11.2, 5.4 Hz, 1H), 1.78 (d, J = 8.0 Hz, 5H), 1.66(d, J = 5.6 Hz, 2H). D161 747.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s,1H), 9.01 (s, 1H), 8.19 (s, 1H, FA salt), 7.60 (s, 1H), 7.52 (d, J = 9.1Hz, 1H), 7.08-7.01 (m, 2H), 6.74 (s, 2H), 6.19 (s, 1H), 5.05 (dd, J =13.3, 5.1 Hz, 1H), 4.33 (d, J = 16.9 Hz, 1H), 4.20 (d, J = 16.9 Hz, 1H),4.00 (t, J = 7.4 Hz, 4H), 3.82 (s, 6H), 3.68 (s, 2H), 3.48 (s, 3H),3.30-3.25 (m, 6H), 3.05 (t, J = 6.5 Hz, 2H), 2.97-2.80 (m, 2H),2.63-2.54 (m, 1H), 2.44-2.26 (m, 7H), 2.00-1.92 (m, 1H). D162 679.1 ¹HNMR (400 MHz, Methanol-d4) δ 9.10 (s, 1H), 8.52 (s, FA, 1H), 7.56 (d, J= 8.3 Hz, 1H), 7.47 (s, 1H), 7.25-7.16 (m, 2H), 6.83 (s, 2H), 6.19 (s,1H), 5.16 (dd, J = 13.4, 5.2 Hz, 1H), 5.11-5.03 (m, 1H), 4.63-4.43 (m,2H), 4.38 (d, J = 23.9 Hz, 4H), 4.08 (d, J = 7.4 Hz, 4H), 4.05 (s, 1H),3.93 (s, 6H), 3.59 (s, 3H), 2.93 (ddd, J = 17.6, 13.5, 5.4 Hz, 1H), 2.80(ddd, J = 17.7, 4.7, 2.4 Hz, 1H), 2.60- 2.37 (m, 3H), 2.19 (dtd, J =12.8, 5.3, 2.4 Hz, 1H), 1.49 (s, 1H). D163 639.2 ¹H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 9.02 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.58(s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.7, 2.4 Hz, 1H), 6.80(s, 2H), 6.44 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.68 (s, 2H),3.88 (s, 6H), 3.46 (s, 3H), 3.13 (s, 3H), 3.05 (s, 6H), 2.95-2.82 (m,1H), 2.63-2.56 (m, 1H), 2.55 (s, 1H), 2.06- 1.95 (m, 1H). D164 791.5 ¹HNMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.54 (s, 1H), 8.15 (s, 0.9H,FA), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.28- 7.23 (m,1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.93 (d, J = 5.1 Hz, 1H), 6.78 (s, 2H),5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.85 (s, 9H), 3.53 (s, 4H), 3.44-3.42(m, 5H), 3.12-3.08 (m, 2H), 2.91-2.87 (m, 1H), 2.85 (d, J = 4.9 Hz, 3H),2.64-2.53 (m, 3H), 2.37-2.32 (m, 3H), 2.04-1.99 (m, 1H), 1.77-1.70 (m,2H), 1.47-1.37 (m, 3H), 1.32- 1.23 (m, 3H). D165 781.45 ¹H NMR (400 MHz,Methanol-d4) δ 8.49 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.4Hz, 1H), 7.33-7.27 (m, 2H), 7.15 (s, 1H), 6.91 (s, 2H), 5.11 (dd, J =12.5, 5.4 Hz, 1H), 4.54 (s, 2H), 3.99 (s, 10H), 3.78 (d, J = 25.5 Hz,3H), 3.63 (s, 3H), 3.53 (s, 8H), 2.97 (d, J = 8.7 Hz, 6H), 2.93-2.66 (m,4H), 2.20-2.11 (m, 1H). D166 822.65 ¹H NMR (400 MHz, Methanol-d4) δ 8.52(s, 1H, FA), 8.50 (d, J = 8.1 Hz, 1H), 7.80-7.71 (m, 1H), 7.42 (dd, J =5.6, 2.3 Hz, 1H), 7.34- 7.28 (m, 1H), 7.23 (d, J = 0.9 Hz, 1H),7.11-7.08 (m, 1H), 6.81 (d, J = 5.0 Hz, 2H), 5.09 (dd, J = 12.7, 5.5 Hz,1H), 4.34-4.27 (m, 2H), 4.26-3.98 (m, 4H), 3.90 (s, 6H), 3.89-3.82 (m,5H), 3.75-3.69 (m, 1H), 3.65 (s, 6H), 2.97 (s, 3H), 2.93-2.78 (m, 2H),2.78-2.61 (m, 4H), 2.14-2.06 (m, 1H), 2.04-1.82 (m, 2H). D167 820.35 ¹HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.51 (s, 1H), 7.82 (dd, J = 8.5,7.2 Hz, 1H), 7.70 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.2Hz, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.86-6.51(m, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.84(s, 6H), 3.52 (s, 3H), 3.49 (s, 2H), 3.13-3.03 (m, 2H), 2.93-2.81 (m,4H), 2.64-2.52 (m, 3H), 2.10-1.99 (m, 4H), 1.92 (s, 5H), 1.83-1.73 (m,2H), 1.55-1.39 (m, 4H). D168 834.5 ¹H NMR (300 MHz, DMSO-d6) δ 11.14 (s,1H), 8.52 (s, 1H), 8.19 (s, 1H, FA), 7.81 (dd, J = 8.5, 7.2 Hz, 1H),7.65 (t, J = 5.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 7.2 Hz,1H), 7.18 (s, 1H), 7.12 (s, 1H), 6.93 (d, J = 5.0 Hz, 1H), 6.72 (s, 2H),5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.80 (s, 6H),3.57 (s, 2H), 3.53 (s, 3H), 3.28-3.13 (m, 2H), 3.09-3.01 (m, 2H),2.95-2.81 (m, 4H), 2.64-2.53 (m, 2H), 2.13 (s, 3H), 2.08-1.97 (m, 1H),1.86 (s, 6H), 1.77 (t, J = 6.7 Hz, 2H), 1.53-1.37 (m, 4H). D169 833.25¹H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.85 (s, 1H), 8.55 (s, 1H),7.82 (t, J = 5.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H),7.16-7.07 (m, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.90-6.80 (m, 3H), 5.03(dd, J = 12.8, 5.3 Hz, 1H), 4.37 (d, J = 12.5 Hz, 1H), 4.19 (dd, J =12.7, 7.8 Hz, 1H), 3.91 (s, 6H), 3.54 (s, 3H), 3.39-3.26 (m, 2H), 3.15(s, 2H), 3.10-3.02 (m, 2H), 3.02-2.76 (m, 5H), 2.67 (d, J = 4.7 Hz, 3H),2.60 (s, 1H), 2.10 (s, 6H), 2.02-1.92 (m, 1H), 1.65- 1.53 (m, 2H),1.51-1.41 (m, 2H), 1.40-1.29 (m, 2H). D170 820.4 ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.52 (d, J = 9.1 Hz, 1H), 8.07-7.67 (m, 2H),7.43 (s, 1H), 7.36 (dd, J = 8.3, 2.2 Hz, 1H), 7.18 (d, J = 14.4 Hz, 1H),7.12 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 6.86 (d, J = 9.4 Hz, 1H), 6.70(s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.40-4.02 (m, 3H), 3.90 (d, J= 6.2 Hz, 3H), 3.79 (s, 3H), 3.53 (d, J = 3.9 Hz, 3H), 3.49 (s, 1H),3.15-3.03 (m, 2H), 2.95-2.87 (m, 1H), 2.85 (d, J = 4.8 Hz, 3H),2.67-2.53 (m, 4H), 2.31-2.25 (m, 2H), 2.11-2.00 (m, 3H), 1.92 (s, 3H),1.82-1.73 (m, 2H), 1.54- 1.36 (m, 4H). D171 866.25 ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.52 (s, 1H), 8.36 (s, 1H, FA), 7.64 (t, J =5.8 Hz, 1H), 7.58 (dd, J = 8.6, 7.0 Hz, 1H), 7.17 (s, 1H), 7.14-7.08 (m,2H), 7.02 (d, J = 7.1 Hz, 1H), 6.96- 6.90 (m, 1H), 6.72 (s, 2H), 6.53(t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.80 (s, 6H), 3.54(s, 2H), 3.53 (s, 3H), 3.28- 3.26 (m, 2H), 3.06-3.00 (m, 2H), 2.90-2.82(m, 4H), 2.62-2.54 (m, 3H), 2.46 (s, 1H), 2.11 (s, 3H), 2.07-1.99 (m,1H), 1.85 (s, 6H), 1.63-1.53 (m, 2H), 1.49-1.40 (m, 2H), 1.36-1.27 (m,2H). D172 834.25 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.83 (s, 1H,TFA), 8.55 (s, 1H), 7.88-7.80 (m, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.35(dd, J = 8.3, 2.3 Hz, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H),6.87 (s, 2H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 4.37 (d, J = 12.6 Hz,1H), 4.24- 4.12 (m, 3H), 3.91 (s, 6H), 3.54 (s, 5H), 3.13-3.03 (m, 2H),2.93- 2.79 (m, 4H), 2.71-2.60 (m, 4H), 2.58-2.56 (m, 1H), 2.13- 1.99 (m,7H), 1.76 (d, J = 6.8 Hz, 2H), 1.53-1.36 (m, 4H). D173 834.25 ¹H NMR(300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.83 (s, 1H, TFA), 8.55 (s, 1H),7.88-7.80 (m, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.3, 2.3 Hz,1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.87 (s, 2H), 5.12 (dd, J= 12.9, 5.3 Hz, 1H), 4.37 (d, J = 12.6 Hz, 1H), 4.24- 4.12 (m, 3H), 3.91(s, 6H), 3.54 (s, 5H), 3.13-3.03 (m, 2H), 2.93- 2.79 (m, 4H), 2.71-2.60(m, 4H), 2.58-2.56 (m, 1H), 2.13- 1.99 (m, 7H), 1.76 (d, J = 6.8 Hz,2H), 1.53-1.36 (m, 4H). D174 844.55 ¹H NMR (400 MHz, DMSO-d6) δ 11.11(s, 1H), 9.04 (s, 1H), 8.15 (s, 1H, FA), 7.83 (d, J = 8.2 Hz, 1H), 7.55(s, 1H), 7.38-7.22 (m, 2H), 6.96 (d, J = 10.0 Hz, 2H), 6.45 (s, 1H),5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.06-4.93 (m, 1H), 3.82 (s, 3H), 3.65(s, 2H), 3.48 (s, 3H), 3.07 (s, 6H), 2.95-2.81 (m, 3H), 2.82-2.72 (m,2H), 2.70- 2.53 (m, 3H), 2.49-2.38 (m, 4H), 2.38-2.13 (m, 5H), 2.11-1.98(m, 1H), 1.84 (dd, J = 11.9, 6.4 Hz, 2H), 1.77-1.41 (m, 7H), 1.22 (t, J= 7.5 Hz, 3H), 1.18-0.98 (m, 2H). D175 812.2 ¹H NMR (400 MHz,Methanol-d4) δ 9.28 (d, J = 1.8 Hz, 1H), 8.57 (s, 1H, FA), 7.96-7.46 (m,2H), 7.39 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 6.85 (d, J =2.0 Hz, 3H), 6.81-6.73 (m, 1H), 5.12 (dd, J = 13.0, 5.3 Hz, 1H),4.67-4.61 (m, 1H), 4.46-4.32 (m, 4H), 4.18- 4.09 (m, 2H), 3.97 (d, J =2.0 Hz, 6H), 3.87-3.78 (m, 2H), 3.67 (d, J = 2.0 Hz, 6H), 3.43-3.39 (m,1H), 3.12-3.04 (m, 1H), 2.99- 2.85 (m, 1H), 2.85-2.75 (m, 1H), 2.68 (d,J = 7.0 Hz, 2H), 2.57- 2.38 (m, 4H), 2.23-2.13 (m, 1H), 1.93-1.84 (m,4H). D176 774.3 ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.18 (s, 1H),8.07 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 7.7 Hz,1H), 7.05 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.9 Hz, 1H), 6.53 (s, 2H),5.86 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.38-4.14 (m,2H), 3.75 (s, 6H), 3.65-3.51 (m, 6H), 3.41 (s, 5H), 3.01-2.84 (m, 3H),2.61 (s, 4H), 2.42-1.87 (m, 9H), 1.80-1.67 (m, 2H), 1.56- 1.37 (m, 2H).D177 746.2 ¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.02 (s, 1H), 8.26(s, 2H, FA), 7.67-7.58 (m, 2H), 7.49 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H),6.74 (s, 2H), 6.20 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J= 17.2 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H),3.82 (s, 6H), 3.64 (s, 2H), 3.49 (s, 3H), 3.35-3.34 (m, 2H), 2.97-2.92(m, 2H), 2.90-2.86 (m, 1H), 2.82-2.73 (m, 3H), 2.66- 2.56 (m, 2H), 2.41(d, J = 4.6 Hz, 1H), 2.37-2.30 (m, 2H), 2.03- 1.96 (m, 1H), 1.83 (t, J =11.0 Hz, 2H), 1.78-1.71 (m, 2H), 1.70- 1.60 (m, 2H). D178 888.2 ¹H NMR(400 MHz, Methanol-d4) δ 9.14 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H),7.55-7.51 (m, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.28-7.23 (m, 1H), 6.88 (d,J = 4.7 Hz, 2H), 6.72 (s, 1H), 5.17-5.07 (m, 1H), 5.02- 4.95 (m, 1H),4.40 (s, 2H), 3.97 (d, J = 4.4 Hz, 6H), 3.88-3.77 (m, 5H), 3.66 (d, J =12.8 Hz, 2H), 3.61 (s, 3H), 3.58 (d, J = 4.8 Hz, 4H), 3.44-3.37 (m, 1H),3.18 (dd, J = 13.2, 10.3 Hz, 2H), 3.13- 2.97 (m, 4H), 2.92-2.83 (m, 1H),2.81-2.78 (m, 1H), 2.76-2.67 (m, 2H), 2.61-2.51 (m, 1H), 2.33-2.22 (m,1H), 2.22-2.08 (m, 6H), 2.09-2.04 (m, 3H), 1.74-1.59 (m, 2H). D179746.25 ¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.02 (s, 1H), 8.24 (s,2H, FA), 7.62 (s, 1H), 7.58-7.48 (m, 3H), 6.74 (s, 2H), 6.20 (s, 1H),5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 4.28 (d, J =17.1 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.82 (s, 6H), 3.67 (s, 2H), 3.48(s, 3H), 3.40-3.37 (m, 2H), 3.04-2.97 (m, 2H), 2.94- 2.87 (m, 1H),2.82-2.74 (m, 3H), 2.65-2.56 (m, 2H), 2.44-2.38 (m, 1H), 2.38-2.30 (m,2H), 2.05-1.97 (m, 1H), 1.89-1.73 (m, 4H), 1.73- 1.60 (m, 2H). D180780.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.04 (s, 1H), 7.85 (dd,J = 8.5, 7.3 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J= 7.2 Hz, 1H), 6.74 (s, 2H), 6.48 (s, 1H), 5.09 (dd, J = 12.8, 5.4 Hz,1H), 4.55 (s, 2H), 4.43 (s, 4H), 3.79 (s, 6H), 3.55 (s, 2H), 3.47 (s,3H), 3.06 (s, 6H), 2.92-2.81 (m, 1H), 2.63-2.54 (m, 5H), 2.48- 2.37 (m,5H), 2.07-1.98 (m, 1H). D181 773.55 ¹H NMR (300 MHz, DMSO-d6) δ 10.96(s, 1H), 8.21 (s, 1H, FA), 8.07 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.8Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 2H), 6.65 (d, J= 9.0 Hz, 1H), 6.52 (s, 2H), 5.85 (d, J = 7.6 Hz, 1H), 5.05 (dd, J =13.2, 5.1 Hz, 1H), 4.25 (dd, J = 22.4 Hz, 2H), 3.90 (d, J = 12.2 Hz,2H), 3.74 (s, 6H), 3.58 (d, J = 6.4 Hz, 6H), 3.55 (s, 3H), 2.95-2.85 (m,3H), 2.82-2.66 (m, 2H), 2.61 (d, J =3.6 Hz, 1H), 2.42-2.28 (m, 1H),2.10-2.03 (m, 4H), 1.99-1.88 (m, 1H), 1.74 (d, J = 9.0 Hz, 2H), 1.64 (d,J = 12.1 Hz, 2H), 1.31-1.10 (m, 5H), 1.05 (d, J = 9.6 Hz, 1H). D182845.25 ¹H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.25 (br s, 1H, TFAsalt), 9.14 (s, 1H), 8.11 (s, 1H), 7.64 (dd, J = 8.4, 2.3 Hz, 1H), 7.20(d, J = 4.5 Hz, 2H), 7.06 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.4, 2.2Hz, 1H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.87 (p, J = 6.7 Hz, 1H),4.48-4.18 (m, 6H), 4.17-4.12 (m, 3H), 3.91 (s, 6H), 3.42 (s, 3H), 3.19(s, 2H), 3.08-2.80 (m, 7H), 2.68-2.55 (m, 2H), 2.43-2.30 (m, 4H),2.11-1.76 (m, 11H), 1.59-1.37 (m, 2H). D183 773.2 ¹H NMR (400 MHz,DMSO-d6) δ 10.99 (s, 1H), 8.21 (s, 1H, FA), 8.07 (d, J = 8.9 Hz, 1H),7.64 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.21(d, J = 7.7 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 6.53 (s, 2H), 5.86 (d, J= 7.7 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 17.3 Hz,1H), 4.28 (d, J = 17.3 Hz, 1H), 3.75 (s, 6H), 3.62-3.54 (m, 6H), 3.41(s, 3H), 3.01-2.87 (m, 5H), 2.68- 2.56 (m, 2H), 2.44-2.24 (m, 4H),2.15-2.00 (m, 5H), 1.80- 1.64 (m, 6H), 1.48 (q, J = 11.8 Hz, 2H). D184776.3 ¹H NMR (300 MHz, Methanol-d4) δ 9.25 (s, 1H), 7.57 (s, 1H), 7.41(d, J = 8.2 Hz, 1H), 6.96-6.72 (m, 5H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H),4.55 (s, 2H), 4.49-4.30 (m, 4H), 4.27-4.07 (m, 2H), 3.99 (d, J = 9.8 Hz,9H), 3.78 (s, 4H), 3.64 (s, 3H), 3.59-3.48 (m, 5H), 3.27- 3.01 (m, 2H),3.00-2.69 (m, 2H), 2.50 (dd, J = 13.1,4.8 Hz, 1H), 2.35-2.00 (m, 5H).

Example 44—Preparation of Compounds D185-D316

In analogy to the procedures described in the examples above, compoundsD185-D316 were prepared using the appropriate starting materials

Compound No. LCMS ¹H NMR D185 829.45 ¹H NMR (400 MHz, Methanol-d4) δ9.02 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 6.88 (s, 2H),6.63-6.50 (m, 2H), 6.31 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H),4.56-4.30 (m, 6H), 4.19 (t, J = 7.5 Hz, 6H), 3.99 (s, 6H), 3.87 (s, 2H),3.77 (s, 2H), 3.59 (s, 3H), 3.57- 3.46 (m, 3H), 3.09-2.85 (m, 3H),2.83-2.74 (m, 1H), 2.58-2.40 (m, 3H), 2.34-2.07 (m, 5H), 1.53 (s, 6H).D186 814.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.57 (s, 1H),8.09 (s, 1H), 7.88 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.81 (s, 2H), 6.68(d, J = 7.9 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.14 (m, 2H),3.81 (s, 6H), 3.67 (d, J = 15.0 Hz, 6H), 3.57 (s, 5H), 2.99 (t, J = 6.9Hz, 2H), 2.96-2.84 (m, 1H), 2.70-2.56 (m, 2H), 2.46-2.38 (m, 2H),2.37-2.17 (m, 5H), 2.06-1.90 (m, 1H), 1.78-1.65 (m, 4H). D187 844.40 ¹HNMR (400 MHz, MeOD) δ 9.11 (s, 1H), 8.49 (s, 3FA, 3H), 7.52- 7.45 (m,2H), 7.21 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.3, 2.4 Hz, 1H), 6.87 (s,2H), 6.21 (s, 1H), 5.17 (d, J = 5.2 Hz, 1H), 4.84-4.78 (m, 1H),4.66-4.60 (m, 1H), 4.50-4.38 (m, 2H), 4.36-4.33(m, 2H), 4.09 (t, J =7.4, 7.4 Hz, 4H), 3.97 (s, 6H), 3.60 (s, 3H), 3.55- 3.48 (m, 1H),3.17-3.08 (m, 1H), 2.96-2.87 (m, 1H), 2.84-2.76 (m, 1H), 2.71-2.59 (m,3H), 2.56-2.44 (m, 4H), 2.44-2.36 (m, 2H), 2.23-2.16 (m, 1H), 2.07-1.91(m, 5H), 1.85-1.77 (m, 4H), 1.57-1.52 (m, 2H), 1.37-1.28 (m, 3H). D188868.30 ¹H NMR (400 MHz, Methanol-d4) δ 9.62 (s, 1H), 8.46 (s, 1H), 8.16(s, 1H, FA), 7.91 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.21-7.16(m, 2H),6.90 (s, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.85-4.82 ( m, 1H),4.51-4.36 (m, 4H), 3.98 (s, 6H), 3.74 (s, 3H), 3.57 (d, J = 12.1 Hz,2H), 3.18 (d, J = 12.3 Hz, 2H), 3.08-2.86 (m, 5H), 2.84- 2.76(m, 3H),2.64-2.46(m, 3H), 2.20 (m, 2H), 2.12-2.06 (m, 1H), 2.1- 1.98(m, 3H),1.97-1.84 (m, 4H), 1.64 (s, 2H). D189 809.20 ¹H NMR (300 MHz,Methanol-d4) δ 9.15 (d, J = 0.7 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.46(s, 1H), 7.28 (d, J = 1.3 Hz, 1H), 7.22 (d, J = 1.3 Hz, 1H), 7.10 (d, J= 7.8 Hz, 2H), 6.42 (s, 1H), 5.18-5.06 (m, 1H), 4.50-4.31 (m, 2H), 3.99(s, 1H), 3.97-3.92 (m, 4H), 3.69- 3.63 (m, 2H), 3.62-3.52 (m, 4H), 3.35(s, 2H), 3.41-3.34 (m, 2H), 3.18-3.07 (m, 7H), 3.02-2.84 (m, 4H),2.87-2.73 (m, 1H), 2.58- 2.39 (m, 1H), 2.24-2.09 (m, 1H), 1.93-1.83 (m,2H), 1.81- 1.70 (m, 2H), 1.69-1.63 (m, 1H), 1.55-1.36 (m, 2H), 1.36-1.23(m, 1H). D190 861.30 ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.41 (s,1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.13 (dd, J =8.3, 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.81 (s, 2H), 5.11 (dd, J =13.3, 5.1 Hz, 1H), 4.88-4.79 (m, 1H), 4.69 (s, 1H), 4.41-4.18 (m, 2H),3.85 (s, 6H), 3.79-3.74 (m, 2H), 3.60 (s, 3H), 3.55 (s, 2H), 3.03- 2.85(m, 3H), 2.64-2.55 (m, 1H), 2.39 (d, J = 13.1 Hz, 9H), 2.14 (d, J = 7.0Hz, 2H), 2.04-1.96 (m, 1H), 1.83-1.55 (m, 9H), 1.26 (s, 6H), 1.18 (s,2H). D191 845.30 ¹H NMR (300 MHz, Methanol-d4) δ 9.04 (s, 1H), 7.68 (s,1H), 7.50 (d, J = 8.3 Hz, 1H), 7.24-7.13 (m, 2H), 6.81 (s, 2H), 5.18 (d,J = 5.1 Hz, 1H), 4.67 (s, 2H), 4.44 (d, J = 5.3 Hz, 4H), 3.95 (s, 6H),3.68 (s, 5H), 3.58 (s, 4H), 3.43 (s, 1H), 3.22 (m, J = 12.3 Hz, 2H),3.10 (d, J = 6.6 Hz, 3H), 3.03 (s, 1H), 2.98-2.85 (m, 2H), 2.83 (s, 1H),2.52 (m, J = 12.9, 4.9 Hz, 2H), 2.32 (s, 3H), 2.21 (s, 1H), 2.10 (d, J =14.3 Hz, 8H), 1.74 (t, J = 12.9 Hz, 2H). D192 829.40 ¹H NMR (400 MHz,Methanol-d4) δ 9.05 (s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H),6.91-6.86 (m, 3H), 6.83-6.77 (m, 1H), 6.27 (s, 1H), 5.14 (dd, J = 13.3,5.1 Hz, 1H), 4.56-4.31 (m, 6H), 4.26-4.11 (m, 6H), 4.00 (s, 6H), 3.82(s, 2H), 3.72 (s, 2H), 3.63-3.46 (m, 6H), 3.11-2.75 (m, 4H), 2.58-2.43(m, 3H), 2.36-2.07 (m, 5H), 1.53 (s, 6H). D193 786.55 ¹H NMR (400 MHz,DMSO-d6) δ 9.30 (d, J = 0.7 Hz, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.8 Hz,1H), 7.38 (s, 1H), 6.87 (d, J = 4.4 Hz, 2H), 6.70 (dd, J = 4.6, 2.3 Hz,2H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 21.9 Hz, 2H),4.36-4.15 (m, 4H), 4.11-4.00 (m, 2H), 3.91 (s, 6H), 3.69 (d, J = 33.2Hz, 4H), 3.57 (s, 3H), 3.38 (s, 3H), 3.25- 3.12 (m, 1H), 3.02-2.81 (m,3H), 2.71-2.56 (m, 2H), 2.38 (dd, J = 13.3, 4.7 Hz, 1H), 2.24-2.05 (m,3H), 1.95 (s, 3H), 1.01 (d, J = 6.4 Hz, 4H). D194 874.30 ¹H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 9.07 (s, 1H), 8.25 (s, 2H, FA), 7.62 (s,1H), 7.49 (d, J = 8.3 Hz, 1H), 7.15-7.04 (m, 2H), 6.69 (d, J = 32.4 Hz,3H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.89- 4.78 (m, 1H), 4.45-4.19 (m,2H), 3.80 (s, 5H), 3.69 (t, J = 4.9 Hz, 4H), 3.56 (s, 3H), 3.51 (s, 3H),2.98-2.82 (m, 3H), 2.71-2.55 (m, 2H), 2.43-2.15 (m, 8H), 2.06 (d, J =8.0 Hz, 6H), 1.77 (dd, J = 11.2, 6.5 Hz, 2H), 1.66-1.51 (m, 6H), 1.45(s, 1H), 1.12-0.99 (m, 2H). D195 911.35 ¹H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 9.29 (s, 1H), 8.17 (s, FA, 1H), 7.82 (d, J = 8.2 Hz, 1H),7.78 (s, 1H), 7.44 (s, 1H), 7.32- 7.24 (m, 2H), 6.74 (s, 2H), 5.12 (dd,J = 12.8, 5.4 Hz, 1H), 5.02- 4.94 (m, 1H), 3.82 (s, 6H), 3.61-3.54 (m,5H), 3.05-2.85 (m, 4H), 2.83-2.69 (m, 2H), 2.64-2.57 (m, 1H), 2.48-2.39(m, 4H), 2.32- 2.21 (m, 1H), 2.09-2.04 (m, 3H), 1.96-1.85 (m, 1H), 1.85-1.74 (m, 2H), 1.55-1.50 (m, 6H), 1.36-1.12 (m, 3H), 1.07-0.92 (m, 4H).D196 956.35 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.08 (s, 1H), 8.17(s, FA, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.32-7.24 (m, 2H),6.73 (s, 2H), 6.65 (s, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.02- 4.94(m, 1H), 3.81 (s, 6H), 3.69 (t, J = 4.7 Hz, 4H), 3.57 (s, 2H), 3.51-3.47(m, 7H), 2.99 (s, 1H), 2.96-2.78 (m, 5H), 2.74-2.69 (m, 1H), 2.64-2.55(m, 2H), 2.46-2.39 (m, 3H), 2.10-2.02 (m, 3H), 1.91-1.76 (m, 3H),1.65-1.46 (m, 6H), 1.35-1.12 (m, 2H). D197 797.65 ¹H NMR (300 MHz, DMSO)δ 10.98 (s, 1H), 9.03 (d, J = 0.7 Hz, 1H), 8.20 (s, FA, 1H), 7.59 (s,1H), 7.41 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 (d,J = 2.3 Hz, 1H), 6.75 (s, 2H), 6.48 (d, J = 0.8 Hz, 1H), 5.10 (dd, J =13.3, 5.0 Hz, 1H), 4.33 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H),3.81 (s, 6H), 3.73 (d, J = 12.2 Hz, 3H), 3.55 (s, 3H), 3.00-2.83 (m,2H), 2.75-2.61 (m, 3H), 2.57- 2.51 (m, 2H), 2.49-2.24 (m, 9H), 2.03-1.94(m, 1H), 1.74 (d, J = 12.4 Hz, 2H), 1.41-1.32 (m, 3H), 1.30-1.16 (m,2H). D198 781.55 ¹H NMR (300 MHz, Methanol-d4) δ 9.25 (d, J = 0.7 Hz,1H), 8.54 (s, 1H), 7.55 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.37-7.28 (m,2H), 6.80 (s, 3H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.50-4.32 (m, 2H),4.10 (s, 2H), 3.92 (s, 6H), 3.77 (d, J = 12.3 Hz, 2H), 3.64 (s, 3H),3.01 (d, J = 23.7 Hz, 4H), 2.90 (dd, J = 13.1, 5.2 Hz, 3H), 2.85-2.75(m, 4H), 2.72 (d, J = 9.3 Hz, 3H), 2.51 (qd, J = 13.2, 4.9 Hz, 1H),2.24-2.13 (m, 1H), 1.88 (d, J = 12.3 Hz, 2H), 1.67-1.30 (m, 5H). D199818.30 ¹H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.71 (s, 1H), 7.41 (d,J = 8.8 Hz, 1H), 6.85 (d, J = 1.7 Hz, 2H), 6.78 (d, J = 6.8 Hz, 1H),6.70 (h, J = 2.3 Hz, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.39-4.10 (m,4H), 3.94 (s, 3H), 3.88 (d, J = 2.2 Hz, 6H), 3.78-3.60 (m, 4H),3.60-3.56 (m, 3H), 3.49-3.38 (m, 4H), 3.13 (d, J = 36.5 Hz, 3H), 2.93(dd, J = 35.7, 13.8 Hz, 4H), 2.67-2.55 (m, 1H), 2.43-2.26 (m, 1H), 2.12(d, J = 13.1 Hz, 2H), 1.97 (d, J = 11.7 Hz, 2H), 1.86 (d, J = 13.0 Hz,3H), 1.78-1.67 (m, 1H), 1.52 (d, J = 37.9 Hz, 4H). D200 819.40 ¹H NMR(300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.06 (s, 1H), 8.16 (t, J = 1.6 Hz,1H, FA), 7.64 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.78 (s, 2H), 6.70-6.61(m, 2H), 6.30 (s, 1H), 5.52 (d, J = 57.4 Hz, 1H), 5.08 (dd, J = 13.3,5.0 Hz, 1H), 4.35 (ddd, J = 21.3, 10.6, 5.8 Hz, 3H), 4.24-4.00 (m, 4H),3.96-3.80 (m, 9H), 3.77-3.62 (m, 3H), 3.58 (s, 4H), 3.50 (s, 3H),3.01-2.81 (m, 2H), 2.78-2.53 (m, 3H), 2.45-2.36 (m, 1H), 2.38-2.25 (m,3H), 2.07-1.90 (m, 1H), 1.80- 1.67 (m, 4H). D201 827.00 ¹H NMR (400 MHz,DMSO-d6) δ 9.04-8.93 (m, 1H), 7.58 (s, 1H), 7.41 (d, 1H), 6.83 (s, 2H),6.72 (d, J = 2.4 Hz, 2H), 6.23 (s, 1H), 5.02 (d, J = 13.1 Hz, 1H), 4.33(t, J = 17.3 Hz, 3H), 4.19 (d, J = 16.7 Hz, 2H), 4.09 (s, 3H), 4.05-3.95(m, 2H), 3.89-3.85 (m, 6H), 3.71 (s, 3H), 3.64 (s, 3H), 3.48 (s, 3H),3.39 (d, J = 23.0 Hz, 4H), 3.25- 3.08 (m, 1H), 3.04-2.77 (m, 3H),2.70-2.56 (m, 1H), 2.43-2.29 (m, 1H), 2.11 (d, J = 13.9 Hz, 2H),2.05-1.80 (m, 3H), 0.67 (s, 4H). D202 637.35 ¹H NMR (300 MHz, DMSO-d6) δ10.95 (s, 1H), 9.01 (s, 1H), 7.60 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H),6.95 (d, J = 8.2 Hz, 2H), 6.77 (s, 2H), 6.17 (s, 1H), 5.04 (dd, J =13.2, 5.1 Hz, 1H), 4.58 (s, 2H), 4.31 (d, J = 16.6 Hz, 1H), 4.17 (d, J =16.7 Hz, 1H), 4.00 (t, J = 7.4 Hz, 4H), 3.85 (s, 6H), 3.46 (s, 3H), 2.98(s, 3H), 2.94-2.82 (m, 1H), 2.64-2.58 (m, 1H), 2.41-2.28 (m, 3H),2.00-1.90 (m, 1H). D203 832.40 ¹H NMR (400 MHz, Methanol-d4) δ 9.36 (s,1H), 7.65 (s, 1H), 7.47- 7.39 (m, 2H), 7.37-7.27 (m, 2H), 6.78 (s, 2H),5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.63 (s, 2H), 4.48-4.33 (m, 2H),3.98-3.87 (m, 8H), 3.76 (d, J = 12.4 Hz, 2H), 3.71-3.64 (m, 4H), 3.62(q, J = 7.0 Hz, 2H), 3.00-2.68 (m, 10H), 2.61-2.54 (m, 2H), 2.53-2.43(m, 1H), 2.29 (ddd, J = 9.8, 6.1, 2.2 Hz, 1H), 2.18 (dtd, J = 12.8, 5.3,2.4 Hz, 1H), 1.87 (d, J = 12.4 Hz, 2H), 1.61-1.50 (m, 3H), 1.47-1.33 (m,4H), 1.18 (t, J = 7.1 Hz, 3H). D204 846.45 ¹H NMR (400 MHz, Methanol-d4)δ 9.35 (s, 1H), 8.54 (s, 1H, Formic acid), 7.68-7.60 (m, 2H), 7.38 (d, J= 0.9 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.4 Hz, 1H),6.76 (s, 2H), 5.06 (dd, J = 12.5, 5.5 Hz, 2H), 4.61 (s, 4H), 4.03 (d, J= 13.2 Hz, 2H), 3.89 (s, 6H), 3.71-3.64 (m, 4H), 3.60 (q, J = 7.0 Hz,2H), 2.98 (t, J = 12.6 Hz, 3H), 2.90-2.80 (m, 3H), 2.79-2.71 (m, 2H),2.71-2.64 (m, 2H), 2.56-2.49 (m, 2H), 2.30-2.24 (m, 1H), 2.13-2.07 (m,1H), 1.85 (d, J = 12.9 Hz, 2H), 1.65-1.58 (m, 1H), 1.56-1.48 (m, 2H),1.44-1.36 (m, 2H), 1.35-1.32 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H). D205855.00 ¹H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.56 (d, J = 2.5 Hz,1H), 7.44-7.37 (m, 1H), 6.84 (s, 2H), 6.75-6.68 (m, 2H), 6.24 (d, J =8.2 Hz, 1H), 5.05-4.96 (m, 1H), 4.37-4.16 (m, 4H), 4.07 (s, 4H), 3.87(s, 6H), 3.67 (d, J = 28.6 Hz, 4H), 3.48 (s, 4H), 3.44 (d, 2H),3.21-3.12 (m, 1H), 3.07-2.80 (m, 6H), 2.70-2.62 (m, 1H), 2.61-2.54 (m,1H), 2.40-2.31 (m, 1H), 2.10 (d, J = 12.3 Hz, 3H), 2.03-1.87 (m, 5H),1.55-1.37 (m, 2H), 0.67 (s, 4H). D206 847.60 ¹H NMR (300 MHz, DMSO-d6) δ10.99 (s, 1H), 9.45-9.14 (m, 1H, TFA), 9.07 (s, 1H), 7.65 (d, J = 2.7Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 6.90 (s, 2H), 6.80-6.63 (m, 2H), 6.34(d, J = 6.0 Hz, 1H), 5.53 (d, J = 56.8 Hz, 1H), 5.08 (dd, J = 13.2, 5.1Hz, 1H), 4.54-4.02 (m, 9H), 3.92 (s, 6H), 3.70 (d, J = 21.7 Hz, 6H),3.52 (s, 3H), 3.31-3.13 (m, 3H), 3.09-2.83 (m, 7H), 2.22-1.68 (m, 8H),1.62-1.38 (m, 2H). D207 843.55 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s,1H), 9.60-9.10 (m, 2H, TFA), 9.03 (s, 1H), 7.62 (d, J = 3.8 Hz, 1H),7.42 (d, J = 8.9, 2.9 Hz, 1H), 6.89 (s, 2H), 6.70 (dq, J = 7.0, 2.4 Hz,2H), 6.23 (d, J = 6.0 Hz, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H),4.44-4.29 (m, 3H), 4.26- 4.16 (m, 3H), 3.98-3.92 (m, 1H), 3.90 (s, 6H),3.83-3.81 (m, 2H), 3.74 (s, 2H), 3.65 (s, 2H), 3.50 (s, 3H), 3.49-3.42(m, 2H), 3.21 (s, 1H), 3.08-2.85 (m, 6H), 2.68-2.60 (m, 1H), 2.48-2.35(m, 2H), 2.18-1.88 (m, 9H), 1.59-1.46 (m, 2H), 1.43 (d, J = 6.2 Hz, 3H).D208 843.80 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.22-9.12 (m, 1H,TFA salt), 9.03 (s, 1H), 7.62 (d, J = 4.1 Hz, 1H), 7.46-7.38 (m, 1H),6.90 (s, 2H), 6.74-6.67 (m, 2H), 6.23 (d, J = 6.3 Hz, 1H), 5.07 (dd, J =13.3, 5.2 Hz, 1H), 4.44-4.16 (m, 5H), 4.00-3.87 (m, 7H), 3.86-3.78 (m,1H), 3.78-3.62 (m, 5H), 3.52-3.49 (m, 5H), 3.21 (s, 1H), 3.09-2.84 (m,7H), 2.70-2.56 (m, 2H), 2.47-2.29 (m, 2H), 2.19-2.06 (m, 3H), 2.03-1.88(m, 6H), 1.54-1.46 (m, 1H), 1.43 (d, J = 6.1 Hz, 3H). D209 873.45 ¹H NMR(300 MHz, Methanol-d4) δ 9.05 (s, 1H), 7.57 (s, 1H), 7.42 (d, J = 8.2Hz, 1H), 6.88 (s, 3H), 6.81 (d, J = 8.1 Hz, 1H), 6.39 (d, J = 6.6 Hz,1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.40 (d, J = 6.0 Hz, 4H), 4.09 (d,J = 9.0 Hz, 2H), 3.98 (s, 7H), 3.95 (s, 1H), 3.83 (s, 2H), 3.75 (s, 2H),3.65 (s, 4H), 3.60 (s, 3H), 3.40 (s, 1H), 3.30 (s, 3H), 3.23 (d, J =12.8 Hz, 2H), 3.14 (d, J = 7.1 Hz, 4H), 2.90 (dd, J = 12.9, 4.9 Hz, 1H),2.79 (d, J = 17.5 Hz, 1H), 2.51 (dd, J = 13.1, 4.9 Hz, 1H), 2.28 (d, J =13.4 Hz, 2H), 2.12 (d, J = 15.8 Hz, 5H), 1.71 (t, J = 13.0 Hz, 2H), 1.56(s, 3H). D210 845.35 ¹H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.32 (s,1H), 7.58 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.78 (s, 2H), 6.69 (d, J =7.6 Hz, 2H), 6.23 (s, 1H), 5.02 (dd, J = 13.2, 5.1 Hz, 1H), 4.32 (d, J =16.9 Hz, 1H), 4.20 (s, 1H), 4.13 (d, J = 9.2 Hz, 2H), 3.91 (d, J = 8.8Hz, 4H), 3.85 (s, 6H), 3.82 (s, 3H), 3.56 (s, 6H), 3.47 (s, 3H), 3.17(s, 3H), 2.84 (d, J = 13.2 Hz, 2H), 2.63 (s, 3H), 2.34 (s, 4H), 2.00 (s,1H), 1.73 (s, 4H), 1.44 (s, 3H). D211 837.25 ¹H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 9.09 (s, 1H), 8.25 (s, 1H, FA), 7.67 (s, 1H), 7.37 (d, J= 8.1 Hz, 1H), 6.75 (s, 2H), 6.67 (s, 2H), 6.44 (s, 1H), 5.08 (dd, J =13.2, 5.1 Hz, 1H), 4.48 (t, J = 12.3 Hz, 4H), 4.35-4.14 (m, 2H), 3.93(d, J = 23.1 Hz, 1H), 3.83 (s, 6H), 3.69 (s, 2H), 3.57 (s, 3H), 3.51 (s,3H), 3.46 (t, J = 7.4 Hz, 2H), 3.02 (s, 2H), 2.97-2.84 (m, 1H),2.64-2.54 (m, 1H), 2.46- 2.33 (m, 3H), 2.28 (s, 5H), 1.98 (d, J = 12.3Hz, 1H), 1.73 (d, J = 5.3 Hz, 4H). D212 815.40 ¹H NMR (400 MHz, DMSO-d6)δ 10.98 (s, 1H), 10.04-9.79 (m, 2H, TFA salt), 9.03 (s, 1H), 7.61 (s,1H), 7.41 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 4.5 Hz, 2H), 6.74-6.67 (m,2H), 6.20 (s, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.46-4.29 (m, 4H),4.27-4.16 (m, 3H), 4.08- 3.99 (m, 2H), 3.97-3.90 (m, 1H), 3.90 (s, 6H),3.86-3.77 (m, 2H), 3.73 (s, 2H), 3.68-3.63 (m, 2H), 3.50 (s, 3H),3.46-3.43 (m, 1H), 3.39-3.32 (m, 2H), 3.23-3.14 (m, 1H), 3.03-2.84 (m,3H), 2.68-2.55 (m, 1H), 2.46-2.30 (m, 2H), 2.12 (d, J = 13.9 Hz, 2H),2.04-1.87 (m, 4H), 1.43 (d, J = 6.2 Hz, 3H). D213 815.40 ¹H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 10.12-9.61 (m, TFA, 2H), 9.03 (s, 1H),7.61 (s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 6.87 (s, 2H), 6.70 (d, 2H), 6.20(s, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.45-4.35 (m, 3H), 4.33-4.16(m, 4H), 4.08-4.02 (m, 2H), 3.97- 3.93 (m, 1H), 3.90 (s, 6H), 3.83-3.81(m, 2H), 3.74 (s, 2H), 3.65 (s, 2H), 3.50 (s, 3H), 3.47 (s, 1H),3.41-3.34 (m, 2H), 3.19 (s, 1H), 3.05-2.95 (m, 3H), 2.64-2.57 (m, 1H),2.48-2.37 (m, 2H), 2.19- 1.85. (m, 6H), 1.43 (d, J = 6.1 Hz, 3H). D214845.50 ¹H NMR (300 MHz, Methanol-d4) δ 9.52 (d, J = 0.8 Hz, 1H), 8.35(s, 1H, FA), 7.73 (s, 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.49 (d, J = 8.3Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.2, 2.4 Hz, 1H), 6.91(s, 2H), 5.16 (dd, J = 13.2, 5.2 Hz, 1H), 4.88-4.76 (m, 2H), 4.48- 4.35(m, 4H), 3.98 (s, 6H), 3.71 (s, 3H), 3.63-3.49 (m, 2H), 3.16- 3.12 (m,2H), 2.90-2.74 (m, 5H), 2.70-2.60 (m, 2H), 2.60-2.44 (m, 3H), 2.29-2.11(m, 1H), 2.11-1.92 (m, 5H), 1.91-1.80 (m, 4H), 1.71-1.45 (m, 2H), 1.39(s, 9H). D215 861.35 ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.02 (s,1H), 7.67 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.33 (d, J = 2.3 Hz, 1H),7.25 (dd, J = 8.6, 2.2 Hz, 1H), 6.82 (s, 2H), 6.21 (s, 1H), 5.07 (dd, J= 12.9, 5.4 Hz, 1H), 4.12-3.97 (m, 6H), 3.87 (s, 6H), 3.79 (s, 2H),3.49-3.41 (m, 10H), 3.02-2.77 (m, 4H), 3.02-2.77 (m, 5H), 2.71-2.50 (m,3H), 2.34 (t, J = 11.3 Hz, 2H), 2.05-1.97 (m, 1H), 1.76 (d, J = 12.6 Hz,2H), 1.62-1.57 (m, 3H), 1.26-1.16 (m, 2H). D216 816.45 ¹H NMR (300 MHz,DMSO-d6) δ 11.10 (s, 1H), 9.31 (s, 1H), 8.17 (s, 1H, FA), 7.86 (s, 1H),7.68 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.25(dd, J = 8.8, 1.7 Hz, 1H), 6.80 (s, 2H), 5.08 (dd, J = 12.7, 5.4 Hz,1H), 3.83 (s, 6H), 3.64 (s, 2H), 3.58 (s, 3H), 3.44-3.40 (m, 8H),2.96-2.87 (m, 3H), 2.86-2.81 (m, 1H), 2.64- 2.58 (m, 1H), 2.55 (s, 1H),2.38-2.29 (m, 2H), 2.24-2.12 (m, 2H), 2.08-1.96 (m, 1H), 1.65 (d, J =11.9 Hz, 2H), 1.45-1.34 (m, 5H), 1.30-1.27 (m, 2H), 1.24-1.09 (m, 2H),0.88 (q, J = 3.6 Hz, 2H). D217 667.30 ¹H NMR (300 MHz, DMSO-d6) δ 10.98(s, 1H), 9.16 (s, 1H), 7.75 (s, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.26 (d,J = 8.8 Hz, 1H), 7.17- 7.11 (m, 1H), 6.78 (s, 1H), 6.74 (s, 2H), 5.10(dd, J = 13.2, 5.2 Hz, 1H), 4.34 (d, J = 16.7 Hz, 1H), 4.20 (d, J = 16.9Hz, 1H), 3.94 (s, 3H), 3.83 (s, 6H), 3.68-3.61 (m, 2H), 3.54 (s, 3H),3.19-3.12 (m, 4H), 2.74 (d, J = 1.9 Hz, 1H), 2.65-2.58 (m, 5H), 2.38 (d,J = 8.0 Hz, 1H), 2.30-2.25 (m, 1H). D218 829.45 ¹H NMR (400 MHz,DMSO-d6) δ 10.95 (s, 1H), 9.25 (br s, TFA, 1H), 9.03 (s, 1H), 7.62 (s,1H), 7.53 (d, J = 8.3, 2.9 Hz, 1H), 6.89 (s, 2H), 6.55-6.45 (m, 2H),6.22 (d, J = 7.8 Hz, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.34-4.15 (m,4H), 4.02 (t, J = 7.4 Hz, 4H), 3.91 (s, 6H), 3.79 (d, J = 8.2 Hz, 2H),3.72 (d, J = 6.9 Hz, 2H), 3.50 (s, 5H), 3.22 (s, 1H), 3.01-2.85 (m, 6H),2.64-2.53 (m, 2H), 2.41- 2.33 (m, 3H), 2.14 (d, 3H) 2.03-1.87 (m, 6H),1.56-1.42 (m, 2H). D219 731.20 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s,1H), 9.28 (s, 1H), 8.23 (s, 1H, FA), 7.80 (s, 1H), 7.64 (d, J = 8.3 Hz,1H), 7.44 (s, 1H), 6.81- 6.72 (m, 3H), 6.65 (dd, J = 8.3, 2.1 Hz, 1H),5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.83 (s, 6H), 3.74 (s, 4H), 3.56 (d, J= 5.4 Hz, 5H), 2.95- 2.82 (m, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.27 (tt,J = 7.8, 3.9 Hz, 1H), 2.06-1.97 (m, 1H), 1.74 (t, J = 5.4 Hz, 4H),1.06-0.94 (m, 4H). D220 717.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s,1H), 9.28 (s, 1H), 8.21 (s, 1H, FA), 7.80 (s, 1H), 7.53-7.42 (m, 2H),6.75 (s, 2H), 6.54- 6.44 (m, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H),4.36-4.13 (m, 2H), 3.83 (s, 6H), 3.63 (s, 4H), 3.56 (s, 5H), 2.90 (ddd,J = 17.0, 13.6, 5.4 Hz, 1H), 2.55 (s, 3H), 2.45 (s, 2H), 2.40-2.30 (m,1H), 2.27 (td, J = 7.8, 3.9 Hz, 1H), 2.05-1.85 (m, 1H), 1.74 (t, J = 5.4Hz, 4H), 1.06-0.94 (m, 4H). D221 819.40 ¹H NMR (300 MHz, MeOD) δ 8.92(s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 6.88 (d, J = 2.1 Hz,1H), 6.79 (dd, J = 6.8, 2.1 Hz, 3H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H),4.60-4.48 (m, 2H), 4.45-4.32 (m, 4H), 4.31-4.09 (m, 6H), 3.95 (s, 6H),3.82-3.74 (m, 4H), 3.64- 3.46 (m, 8H), 3.27-3.03 (m, 2H), 3.00-2.73 (m,2H), 2.61-2.35 (m, 3H), 2.30-2.04 (m, 5H). D222 845.45 ¹H NMR (400 MHz,Methanol-d4) δ 9.04 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H),7.36 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.7, 2.4 Hz, 1H), 6.88 (s, 2H),6.28 (s, 1H), 5.09 (dd, J = 12.5, 5.4 Hz, 1H), 4.56 (d, J = 13.5 Hz,1H), 4.44 (d, J = 13.8 Hz, 1H), 4.16 (t, J = 7.5 Hz, 4H), 4.07 (d, J =13.2 Hz, 2H), 3.99 (s, 6H), 3.85-3.76 (m, 1H), 3.59 (s, 3H), 3.01 (t, J= 12.3 Hz, 3H), 2.92-2.82 (m, 2H), 2.80- 2.73 (m, 2H), 2.73-2.66 (m,2H), 2.50 (p, J = 7.5 Hz, 2H), 2.17- 2.09 (m, 1H), 1.89 (d, J = 12.9 Hz,2H), 1.78-1.69 (m, 1H), 1.57 (d, J = 7.1 Hz, 8H), 1.45-1.27 (m, 4H),0.91 (d, J = 7.0 Hz, 1H). D223 794.45 ¹H NMR (300 MHz, DMSO-d6) δ 10.96(s, 1H), 9.05 (s, 1H), 7.58 (s, 1H), 7.52 (d, J = 9.1 Hz, 1H), 7.06 (m,2H), 6.90 (s, 2H), 6.52 (s, 1H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.32(d, J = 17.0 Hz, 2H), 4.19 (d, J = 16.8 Hz, 2H), 3.89 (s, 2H), 3.85-3.76(m, 8H), 3.56-3.43 (m, 2H), 3.23-3.04 (m, 12H), 2.99-2.89 (m, 1H),2.88-2.76 (m, 2H), 2.66-2.54 (m, 1H), 2.44-2.32 (m, 1H), 2.01-1.91 (m,1H), 1.81-1.71 (m, 2H), 1.65-1.49 (m, 3H), 1.34-1.17 (m, 2H). D224778.40 ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.16 (s, 1H), 7.73 (s,1H), 7.49 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.74 (d, J =20.0 Hz, 3H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.8 Hz,1H), 4.19 (d, J = 16.8 Hz, 1H), 3.93 (s, 3H), 3.85 (d, J = 12.7 Hz, 2H),3.79 (s, 6H), 3.54 (d, J = 5.1 Hz, 5H), 2.90 (ddd, J = 17.8, 13.5, 5.5Hz, 1H), 2.79 (t, J = 12.2 Hz, 2H), 2.69-2.55 (m, 1H), 2.47- 2.36 (m,5H), 2.36-2.23 (m, 6H), 2.01-1.91 (m, 1H), 1.73 (d, J = 12.6 Hz, 2H),1.50 (s, 1H), 1.43-1.30 (m, 2H), 1.23-1.12 (m, 2H). D225 778.45 ¹H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.16 (s, 1H), 7.73 (s, 1H), 7.41 (d,J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz,1H), 6.74 (d, J = 20.0 Hz, 3H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H),4.38-4.15 (m, 2H), 3.93 (s, 3H), 3.79 (s, 6H), 3.73 (d, J = 12.3 Hz,3H), 3.57-3.52 (m, 5H), 2.97-2.84 (m, 1H), 2.75-2.64 (m, 2H), 2.64-2.55(m, 1H), 2.48-2.38 (m, 4H), 2.38-2.20 (m, 6H), 2.03-1.94 (m, 1H), 1.74(d, J = 12.4 Hz, 2H), 1.52-1.42 (m, 1H, 1.41-1.32 (m, 2H), 1.31-1.17 (m,2H). D226 717.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.29 (s,1H), 8.15 (s, 1H, FA), 7.81 (s, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.1 Hz,1H), 6.78 (s, 2H), 6.70 (d, J = 7.9 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz,1H), 4.36-4.15 (m, 2H), 3.86 (s, 6H), 3.76 (s, 2H), 3.61 (s, 4H), 3.57(s, 4H), 2.98-2.84 (m, 1H), 2.71-2.65 (m, 2H), 2.60 (d, J = 16.6 Hz,2H), 2.38 (dd, J = 13.3, 4.5 Hz, 1H), 2.30-2.21 (m, 1H), 1.98 (d, J =13.1 Hz, 1H), 1.83 (s, 4H), 1.05-0.96 (m, 4H). D227 865.55 ¹H NMR (300MHz, Methanol-d4) δ 9.11 (d, J = 0.8 Hz, 1H), 8.56 (s, 0.47H, FA),7.50-7.39 (m, 2H), 6.90-6.77 (m, 4H), 6.22 (s, 1H), 5.15 (dd, J = 13.3,5.1 Hz, 1H), 4.48-4.39 (m, 2H), 4.33 (d, J = 5.4 Hz, 2H), 4.09 (t, J =7.5 Hz, 4H), 4.03-3.99 (m, 2H), 3.97 (s, 6H), 3.73 (d, J = 7.6 Hz, 2H),3.60 (s, 3H), 3.56-3.47 (m, 2H), 3.00- 2.91 (m, 1H), 2.90-2.82 (m, 1H),2.81-2.74 (m, 1H), 2.74-2.63 (m, 2H), 2.60-2.40 (m, 6H), 2.39-2.31 (m,2H), 2.22-2.12 (m, 3H), 2.03 (d, J = 14.3 Hz, 2H), 1.97-1.87 (m, 1H),1.55-1.41 (m, 2H). D228 847.45 ¹H NMR (300 MHz, Methanol-d4) δ 9.49 (s,1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.24-7.13 (m,2H), 6.90 (s, 2H), 5.15 (dd, J = 13.2, 5.2 Hz, 1H), 4.54-4.35 (m, 4H),3.98 (s, 6H), 3.72 (s, 3H), 3.70-3.61 (m, 4H), 3.56-3.46 (m, 1H),3.45-3.33 (m, 1H), 3.21-3.19 (m, 1H), 3.14-2.97 (m, 4H), 2.96-2.80 (m,1H), 2.77-2.67 (m, 2H), 2.58-2.47 (m, 2H), 2.31-2.12 (m, 2H), 2.17-1.96(m, 8H), 1.77-1.66 (m, 2H), 1.60 (s, 6H). D229 692.15 ¹H NMR (300 MHz,DMSO-d6) δ 11.13 (s, 1H), 9.30 (s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.52(s, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.82 (s, 2H), 5.24-5.05 (m, 1H), 5.00(s, 1H), 4.00-3.67 (m, 10H), 3.58 (s, 3H), 3.32-3.27 (m, 2H), 3.02-2.78(m, 1H), 2.67-2.54 (m, 2H), 2.14-1.97 (m, 1H), 1.40 (s, 3H), 1.33-1.20(m, 2H), 0.96- 0.80 (m, 2H). D230 781.25 ¹H NMR (400 MHz, Methanol-d4) δ9.26 (d, J = 0.8 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.56 (s, 1H), 7.12(d, J = 7.3 Hz, 2H), 6.88-6.79 (m, 3H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H),4.49-4.34 (m, 4H), 4.01 (s, 3H), 3.96 (s, 6H), 3.93 (s, 2H), 3.51-3.47(m, 4H), 3.41-3.34 (m, 4H), 3.09 (t, J = 7.6 Hz, 2H), 2.98-2.85 (m, 3H),2.84-2.74 (m, 1H), 2.55-2.40 (m, 1H), 2.21-2.12 (m, 1H), 1.88 (d, J =12.8 Hz, 2H), 1.70-1.66 (m, 3H), 1.42 (q, J = 10.8 Hz, 2H). D231 781.30¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.18 (s, 1H), 7.72 (s, 1H),7.44 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.6, 2.3 Hz, 1H), 7.19 (s, 1H),6.84 (s, 2H), 6.78 (s, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.43-4.14(m, 2H), 3.95 (s, 3H), 3.87 (s, 6H), 3.77 (d, J = 12.0 Hz, 2H),3.17-3.00 (m, 8H), 2.98-2.85 (m, 2H), 2.80-2.69 (m, 2H), 2.65-2.52 (m,3H), 2.43-2.28 (m, 2H), 1.99 (d, J = 10.8 Hz, 1H), 1.78 (d, J = 12.5 Hz,2H), 1.61-1.45 (m, 3H), 1.35-1.27 (m, 2H). D232 865.45 ¹H NMR (400 MHz,DMSO-d6 with a drop of D2O) δ 8.91 (s, 1H), 7.63-7.49 (m, 2H), 6.77 (d,J = 2.2 Hz, 2H), 6.62-6.53 (m, 2H), 6.21 (d, J = 6.8 Hz, 1H), 4.92 (dd,J = 13.2, 5.2 Hz, 1H), 4.38-4.22 (m, 2H), 3.99 (t, J = 7.5 Hz, 6H),3.86-3.75 (m, 8H), 3.53-3.36 (m, 6H), 3.20-2.74 (m, 5H), 2.87-2.70 (m,3H), 2.71-2.57 (m, 2H), 2.34 (t, 3H), 2.24 (s, 2H), 2.01 (s, 2H),1.91-1.70 (m, 3H), 1.43 (d, J = 12.9 Hz, 2H). D233 720.35 ¹H NMR (300MHz, DMSO-d6) δ 10.98 (s, 1H), 9.29 (s, 1H), 8.14 (s, 1H, FA), 7.80 (s,1H), 7.44 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 6.75 (s, 2H), 6.69 (d, J =8.1 Hz, 2H), 5.09 (dd, J = 13.2, 5.2 Hz, 1H), 4.41-4.06 (m, 2H), 3.84(s, 6H), 3.59 (s, 6H), 2.95-2.84 (m, 1H), 2.64-2.61 (m, 2H), 2.42-2.34(m, 4H), 2.05-1.92 (m, 2H), 1.76 (s, 4H), 1.01 (s, 4H). D234 710.35 ¹HNMR (300 MHz, Methanol-d4) δ 9.26 (s, 1H), 7.58 (s, 1H), 7.42 (d, J =8.2 Hz, 1H), 6.89 (d, J = 4.7 Hz, 3H), 6.85-6.79 (m, 2H), 5.15 (dd, J =13.2, 5.1 Hz, 1H), 4.49-4.32 (m, 4H), 4.00 (d, J = 7.0 Hz, 9H), 3.87 (s,2H), 3.74 (s, 2H), 3.64-3.52 (m, 2H), 3.29-3.19 (m, 2H), 3.01-2.86 (m,1H), 2.85-2.74 (m, 1H), 2.60-2.41 (m, 1H), 2.36-2.25 (m, 2H), 2.24-2.04(m, 3H). D235 666.30 ¹H NMR (300 MHz, Methanol-d4) δ 9.25 (s, 1H), 8.56(d, 1H, FA), 7.79 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.48(d, J = 8.1 Hz, 1H), 6.94-6.78 (m, 3H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H),4.51 (d, J = 5.0 Hz, 2H), 4.37-4.24 (m, 2H), 4.01 (s, 3H), 3.97 (s, 6H),3.65 (s, 3H), 3.57 (d, J = 12.0 Hz, 2H), 3.16-2.97 (m, 3H), 2.97- 2.86(m, 1H), 2.86-2.75 (m, 1H), 2.51 (qd, J = 13.1, 4.7 Hz, 1H), 2.27-2.15(m, 1H), 2.15-2.03 (m, 4H). D236 853.35 ¹H NMR (300 MHz, DMSO-d6) δ10.98 (s, 1H), 9.04 (s, 1H), 8.24 (s, 0.3H, FA), 7.60 (s, 1H), 7.37 (d,J = 8.1 Hz, 1H), 6.78 (s, 2H), 6.72-6.64 (m, 2H), 6.49 (s, 1H), 5.08(dd, J = 13.2, 5.1 Hz, 1H), 4.31 (d, J = 16.5 Hz, 1H), 4.18 (d, J = 16.6Hz, 1H), 3.82 (s, 6H), 3.66 (s, 2H), 3.58 (s, 4H), 3.48 (s, 3H), 3.07(s, 6H), 2.99-2.82 (m, 3H), 2.64-2.54 (m, 2H), 2.47-2.35 (m, 4H),2.29-2.13 (m, 4H), 2.02-1.84 (m, 3H), 1.79-1.67 (m, 4H), 1.36-1.23 (m,1H). D237 802.30 ¹H NMR (300 MHz, MeOD) δ 9.41 (d, J = 0.8 Hz, 1H), 7.74(s, 1H), 7.62-7.50 (m, 2H), 7.44-7.34 (m, 2H), 6.92 (d, J = 3.9 Hz, 2H),5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.58-4.36 (m, 4H), 4.08-3.97 (m, 6H),3.95-3.85 (m, 1H), 3.77-3.54 (m, 7H), 3.45-3.35 (m, 3H), 3.32-3.25 (m,2H), 3.24-3.09 (m, 3H), 3.02-2.69 (m, 2H), 2.61- 2.40 (m, 1H), 2.24-2.17(m, 1H), 2.12-1.89 (m, 3H), 1.85-1.79 (m, 2H), 1.71-1.58 (m, 2H), 1.47(s, 3H), 1.38-1.26 (m, 3H), 0.98- 0.88 (m, 2H). D238 802.25 ¹H NMR (300MHz, Methanol-d4) δ 9.41 (d, J = 0.8 Hz, 1H), 7.80- 7.68 (m, 2H),7.64-7.56 (m, 1H), 7.24-7.15 (m, 2H), 6.93 (d, J = 4.2 Hz, 2H), 5.14(dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.36 (m, 4H), 4.30-4.02 (m, 1H), 4.00(d, J = 4.3 Hz, 6H), 3.82 (s, 4H), 3.70- 3.64 (m, 3H), 3.47-3.35 (m,2H), 3.30-3.20 (m, 3H), 3.18-3.07 (m, 3H), 3.02-2.78 (m, 2H), 2.57-2.39(m, 1H), 2.27-2.11 (m, 1H), 2.10-1.90 (m, 3H), 1.82 (s, 3H), 1.68-1.52(m, 2H), 1.48 (s, 3H), 1.38-1.25 (m, 2H), 1.00-0.90 (m, 2H). D239 657.35¹H NMR (300 MHz, Methanol-d4) δ 7.70 (s, 1H), 6.04 (d, J = 9.4 Hz, 2H),5.76-5.64 (m, 2H), 5.31 (s, 2H), 5.25 (s, 1H), 3.75-3.57 (m, 2H),3.25-3.19 (m, 2H), 3.15-3.05 (m, 2H), 3.00-2.89 (m, 2H), 2.89-2.75 (m,2H), 2.50-2.34 (m, 9H), 1.45-1.20 (m, 2H), 1.08- 0.89 (m, 1H), 0.73-0.59(m, 1H). D240 794.50 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.04 (s,1H), 8.29 (s, 1H, FA), 7.58 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.28-7.21(m, 1H), 7.17-7.11 (m, 1H), 6.75 (s, 2H), 6.49 (s, 1H), 5.10 (dd, J =13.3, 5.1 Hz, 1H), 4.36-4.16 (m, 2H), 3.80 (s, 6H), 3.78-3.69 (m, 3H),3.56-3.49 (m, 3H), 3.07 (s, 6H), 2.96-2.86 (m, 1H), 2.74- 2.69 (m, 1H),2.66-2.54 (m, 3H), 2.47-2.34 (m, 5H), 2.32-2.23 (m, 3H), 2.02-1.95 (m,1H), 1.78-1.70 (m, 2H), 1.48-1.33 (m, 3H), 1.31-1.21 (m, 2H). D241879.50 ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.10 (s, 1H), 8.15 (s,1H, FA), 7.69 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 6.69 (d,J = 7.3 Hz, 2H), 6.48 (s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.49 (t,J = 12.3 Hz, 4H), 4.32 (d, J = 16.7 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H),3.86 (s, 9H), 3.60 (s, 4H), 3.52 (s, 4H), 3.11-3.05 (m, 4H), 2.95-2.84(m, 2H), 2.65-2.56 (m, 2H), 2.47-2.34 (m, 2H), 2.03-1.93 (m, 1H),1.83-1.77 (m, 4H), 1.72 (d, J = 12.0 Hz, 2H), 1.48-1.20 (m, 6H). D242657.30 ¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.29 (s, 1H, TFA),9.17 (s, 1H), 7.77-7.66 (m, 2H), 7.24-6.99 (m, 2H), 6.80 (d, J = 30.9Hz, 3H), 5.33-5.02 (m, 2H), 4.81-4.55 (m, 2H), 4.55-4.13 (m, 6H),4.00-3.82 (m, 9H), 3.02-2.85 (m, 1H), 2.63 (s, 1H), 2.44- 2.31 (m, 1H),2.08-1.93 (m, 1H). D243 897.60 ¹H NMR (300 MHz, Methanol-d4) δ 9.38 (s,1H), 8.57 (s, FA, 1H), 7.66 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.38 (d,J = 0.9 Hz, 1H), 7.23- 7.12 (m, 2H), 6.83 (s, 2H), 5.17 (dd, 1H),4.83-4.76 (m, 1H), 4.67-4.60 (m, 1H), 4.50-4.36 (m, 2H), 4.23-4.07 (m,2H), 3.95 (s, 6H), 3.68 (s, 3H), 3.07-2.75 (m, 7H), 2.66-2.40 (m, 6H),2.29- 2.12 (m, 3H), 2.03-1.83 (m, 4H), 1.77-1.49 (m, 6H), 1.14- 1.03 (m,4H). D244 803.95 ¹H NMR (300 MHz, Methanol-d4) δ 8.99 (d, J = 0.7 Hz,1H), 7.62- 7.46 (m, 4H), 6.87 (s, 2H), 6.37 (s, 1H), 5.17 (dd, J = 13.3,5.2 Hz, 1H), 4.57-4.39 (m, 4H), 4.21 (t, J = 7.6 Hz, 4H), 3.97 (s, 6H),3.79 (d, J = 12.3 Hz, 2H), 3.60 (s, 3H), 3.55-3.49 (m, 4H), 3.42-3.36(m, 4H), 3.14-3.00 (m, 4H), 2.96-2.75 (m, 1H), 2.60-2.46 (m, 3H),2.24-2.14 (m, 1H), 2.04-1.93 (m, 2H), 1.76-1.70 (m, 3H), 1.61-1.51 (m,2H). D245 804.10 ¹H NMR (300 MHz, Methanol-d4) δ 9.10 (d, J = 0.7 Hz,1H), 8.52 (s, 1H, FA), 7.67-7.58 (m, 1H), 7.45 (s, 1H), 7.08 (d, J = 8.2Hz, 2H), 6.82 (s, 2H), 6.22 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H),4.49- 4.31 (m, 2H), 4.14-4.03 (m, 6H), 4.01-3.85 (m, 8H), 3.59 (s, 3H),3.07 (s, 4H), 2.95-2.61 (m, 9H), 2.53-2.37 (m, 3H), 2.15 (dd, J = 12.7,4.9 Hz, 1H), 1.85 (d, J = 12.6 Hz, 2H), 1.61-1.55 (m, 3H), 1.37 (q, J =12.5, 11.5 Hz, 2H). D246 942.50 ¹H NMR (400 MHz, Methanol-d4) δ 9.20 (s,1H), 8.55 (s, FA, 1H), 7.48 (t, J = 4.1 Hz, 2H), 7.20 (d, J = 2.4 Hz,1H), 7.15 (d, J = 7.8 Hz, 1H), 6.87 (s, 2H), 6.64 (s, 1H), 5.16 (dd, J =13.4, 5.1 Hz, 1H), 4.83- 4.72 (m, 1H), 4.51-4.32 (m, 4H), 3.97 (s, 6H),3.78 (t, J = 4.9 Hz, 4H), 3.68-3.49 (m, 9H), 3.21-3.04 (m, 2H),3.02-2.75 (m, 5H), 2.72-2.42 (m, 5H), 2.42-2.26 (m, 1H), 2.24-2.00 (m,3H), 1.97- 1.86 (m, 2H), 1.81-1.45 (m, 6H). D247 667.35 ¹H NMR (300 MHz,Methanol-d4) δ 9.39 (s, 1H), 7.72 (s, 1H), 7.63- 7.57 (m, 1H), 7.38 (d,J = 4.4 Hz, 1H), 7.32-7.19 (m, 2H), 6.89 (s, 2H), 5.17 (dd, J = 13.4,5.2 Hz, 2H), 4.83-4.74 (m, 1H), 4.67 (d, J = 15.1 Hz, 2H), 4.51-4.30 (m,4H), 3.98 (d, J = 16.9 Hz, 6H), 3.79- 3.54 (m, 1H), 3.01-2.77 (m, 2H),2.60-2.45 (m, 1H), 2.25-2.13 (m, 2H), 1.11 (d, J = 8.9 Hz, 4H). D248839.40 ¹H NMR (300 MHz, Methanol-d4) δ 9.19 (d, J = 0.8 Hz, 1H), 8.54(s, 1H, FA), 7.67-7.58 (m, 1H), 7.52 (s, 1H), 7.11-7.04 (m, 2H), 6.81(s, 2H), 6.43 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.50-4.31 (m,6H), 4.05 (s, 2H), 3.95 (s, 1H), 3.92 (s, 7H), 3.62 (s, 3H), 3.13- 2.99(m, 4H), 2.95-2.73 (m, 8H), 2.68 (s, 2H), 2.56-2.37 (m, 1H), 2.25-2.08(m, 1H), 1.85 (d, J = 12.7 Hz, 2H), 1.61-1.55 (m, 3H), 1.45-1.28 (m,2H). D249 658.81 D250 632.41 D251 686.53 D252 686.46 D253 646.48 D254698.35 ¹H NMR (400 MHz, Methanol-d4) δ 9.25 (s, 1H), 8.55 (s, 1H, FA),7.58 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 6.88(s, 2H), 6.83 (s, 1H), 5.16 (dd, J = 13.4, 5.1 Hz, 1H), 4.60 (d, J =13.5 Hz, 1H), 4.52-4.37 (m, 3H), 4.00 (d, J = 7.0 Hz, 9H), 3.89- 3.85(m, 2H), 3.64-3.59 (m, 2H), 3.48-3.33 (m, 2H), 2.95-2.86 (m, 1H), 2.81(d, J = 17.2 Hz, 1H), 2.59-2.44 (m, 1H), 2.23-2.16 (m, 1H), 1.62 (d, J =6.4 Hz, 6H). D255 708.45 ¹H NMR (300 MHz, Methanol-d4) δ 9.16 (s, 1H),8.56 (s, 1H, FA), 7.51 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.35 (d, J =7.1 Hz, 2H), 6.88 (s, 2H), 6.52 (s, 1H), 5.16 (dd, J = 13.2, 5.1 Hz,1H), 4.64 (s, 2H), 4.52-4.35 (m, 2H), 4.25 (br s, 2H), 3.97 (s, 6H),3.68-3.54 (m, 4H), 3.45-3.37 (m, 2H), 3.14 (s, 7H), 3.03-2.73 (m, 2H),2.59- 2.43 (m, 1H), 2.27-2.14 (m, 1H), 1.63 (s, 6H). D256 692.20 ¹H NMR(300 MHz, Methanol-d4) δ 9.09 (d, J = 3.5 Hz, 1H), 8.56 (s, 1H),7.67-7.37 (m, 2H), 7.21 (dd, J = 8.4, 2.3 Hz, 1H), 7.11 (s, 1H), 6.85(s, 2H), 6.18 (s, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.26 (m,7H), 4.15-4.00 (m, 6H), 3.94 (s, 6H), 3.58 (d, J = 1.3 Hz, 3H), 2.96 (s,3H), 2.95-2.87 (m, 1H), 2.85-2.73 (m, 1H), 2.55-2.29 (m, 3H), 2.25-2.12(m, 1H). D257 637.15 ¹H NMR (300 MHz, Methanol-d4) δ 9.14 (d, J = 0.7Hz, 1H), 7.46- 7.36 (m, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.86 (dd, J =8.2, 2.2 Hz, 1H), 6.73 (s, 2H), 6.52 (d, J = 0.8 Hz, 1H), 5.15 (dd, J =13.2, 5.2 Hz, 1H), 4.55-4.33 (m, 5H), 4.14-4.00 (m, 2H), 3.80 (s, 6H),3.58 (s, 3H), 3.12 (s, 6H), 2.98-2.86 (m, 1H), 2.85-2.76 (m, 1H), 2.57-2.44 (m, 1H), 2.24-2.13 (m, 1H). D258 818.42 ¹H NMR (400 MHz, DMSO-d6) δ10.98 (s, 1H), 9.15 (s, 1H), 8.21 (s, 1H, FA salt), 7.72 (s, 1H), 7.41(d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 (d, J = 2.3Hz, 1H), 6.76 (s, 1H), 6.70 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H),4.33-4.20 (m, 2H), 3.94 (s, 3H), 3.79 (s, 6H), 3.75 (d, J = 12.1 Hz,3H), 3.53 (s, 4H), 2.98-2.85 (m, 1H), 2.75-2.65 (m, 2H), 2.64-2.55 (m,1H), 2.48-2.43 (m, 3H), 2.43-2.30 (m, 8H), 2.04-1.95 (m, 1H), 1.82-1.74(m, 6H), 1.52- 1.40 (m, 3H), 1.35-1.22 (m, 2H). D259 815.45 ¹H NMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 8.26 (s, 1H, FA), 7.58 (s, 1H), 7.37 (d, J= 8.2 Hz, 1H), 6.77 (s, 2H), 6.72-6.65 (m, 2H), 6.17 (s, 1H), 5.12 (dd,J = 13.4, 5.1 Hz, 1H), 4.35-4.13 (m, 2H), 4.04-3.94 (m, 6H), 3.84 (s,6H), 3.78-3.69 (m, 2H), 3.57 (s, 4H), 3.48 (s, 3H), 3.41-3.34 (m, 2H),2.99 (s, 3H), 2.97-2.90 (m, 1H), 2.80-2.65 (m, 2H), 2.51-2.45 (m, 2H),2.42-2.23 (m, 7H), 2.04- 1.94 (m, 1H), 1.76-1.69 (m, 4H). D260 695.35 ¹HNMR (400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.56 (s, 0.49H, FA), 7.57 (s,1H), 7.50 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.83 (d, J =5.9 Hz, 3H), 5.16 (dd, J = 13.4, 5.2 Hz, 1H), 4.46-4.39 (m, 2H),4.28-4.11 (m, 2H), 4.01 (s, 3H), 3.96 (s, 6H), 3.65 (s, 4H), 3.42-3.36(m, 2H), 3.30-3.18 (m, 3H), 2.95-2.89 (m, 1H), 2.83- 2.77 (m, 1H),2.54-2.47 (m, 1H), 2.22-2.16 (m, 1H), 1.62 (s, 6H). D261 879.35 ¹H NMR(300 MHz, Methanol-d4) δ 9.20 (d, J = 0.7 Hz, 1H), 7.53 (s, 1H), 7.39(d, J = 8.2 Hz, 1H), 6.85 (s, 3H), 6.78 (dd, J = 8.2, 2.3 Hz, 1H), 6.43(s, 1H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.53-4.28 (m, 6H), 4.26 (s,2H), 3.96 (s, 7H), 3.67 (s, 4H), 3.62 (s, 3H), 3.43 (s, 2H), 3.16 (s,3H), 2.95 (d, J = 12.0 Hz, 3H), 2.48 (s, 5H), 2.30 (d, J = 6.8 Hz, 2H),2.17 (dd, J = 8.3, 3.6 Hz, 1H), 2.00 (d, J = 14.1 Hz, 2H), 1.90 (s, 5H),1.49 (s, 2H). D262 634.30 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H),9.02 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.34-7.25 (m, 3H),7.21 (d, J = 2.4 Hz, 1H), 7.00-6.92 (m, 2H), 6.39 (s, 1H), 5.11 (dd, J =13.3, 5.1 Hz, 1H), 4.40-4.15 (m, 2H), 4.03-3.81 (m, 3H), 3.46 (s, 3H),3.06 (s, 6H), 2.99-2.85 (m, 3H), 2.78 (s, 3H), 2.70-2.58 (m, 1H),2.44-2.32 (m, 1H), 2.05-1.95 (m, 1H), 1.97-1.80 (m, 2H), 1.75 (d, J =12.0 Hz, 2H). D263 672.35 ¹H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ9.28 (s, 1H), 8.22 (s, 1H, FA), 7.78 (s, 1H), 7.69-7.59 (m, 3H), 7.40(s, 1H), 6.74 (s, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.51-4.32 (m,2H), 3.83 (s, 6H), 3.63 (s, 2H), 3.56 (s, 6H), 3.20 (t, J = 6.5 Hz, 2H),2.97- 2.85 (m, 1H), 2.64-2.57 (m, 1H), 2.46-2.37 (m, 1H), 2.28- 2.19 (m,1H), 2.06-1.97 (m, 1H), 0.98 (t, J = 6.1 Hz, 4H). D264 730.45 ¹H NMR(300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H, TFAsalt), 7.59 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.08 (s, 2H), 6.75-6.67(m, 2H), 6.17 (s, 1H), 5.08 (dd, J = 13.2, 5.0 Hz, 1H), 4.34 (s, 2H),4.31 (s, 1H), 4.20 (d, J = 16.7 Hz, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.93(s, 3H), 3.79 (s, 2H), 3.65 (s, 2H), 3.50 (s, 3H), 3.45- 3.34 (m, 2H),3.33-3.15 (m, 2H), 2.88-2.75 (m, 3H), 2.66-2.54 (m, 1H), 2.44-2.30 (m,3H), 2.20-2.09 (m, 2H), 2.08-1.94 (m, 3H), 1.22 (t, J = 7.4 Hz, 3H).D265 665.30 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.04 (s, 1H),7.57 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36-7.29 (m, 1H), 7.20 (d, J =2.3 Hz, 1H), 6.75 (s, 2H), 6.55-6.49 (m, 1H), 5.11 (dd, J = 13.3, 5.1Hz, 1H), 4.39-4.19 (m, 2H), 3.89-3.83 (m, 2H), 3.81 (s, 6H), 3.48 (s,3H), 3.45-3.37 (m, 2H), 3.08 (s, 6H), 2.99-2.86 (m, 1H), 2.82-2.70 (m,2H), 2.65-2.56 (m, 1H), 2.47-2.35 (m, 2H), 2.06- 1.96 (m, 1H), 1.61-1.53(m, 2H). D266 707.20 ¹H NMR (300 MHz, Methanol-d4) δ 9.48 (s, 1H), 8.55(s, 1H, FA), 7.85-7.69 (m, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.08-6.93 (m,2H), 6.86 (s, 2H), 5.24-5.06 (m, 1H), 4.82 (s, 2H), 4.63 (d, J = 8.0 Hz,2H), 4.46-4.26 (m, 2H), 3.92-3.83 (m, 6H), 3.76-3.69 (m, 4H), 3.65 (d, J= 20.3 Hz, 3H), 3.56-3.46 (m, 2H), 3.29-3.17 (m, 2H), 2.97-2.73 (m, 2H),2.60-2.41 (m, 1H), 2.39-2.12 (m, 3H), 2.03- 1.85 (m, 2H). D267 675.35 ¹HNMR (400 MHz, Methanol-d4) δ 9.13 (d, J = 0.7 Hz, 1H), 8.52 (0.3H, FA),7.77 (d, J = 1.3 Hz, 1H), 7.65 (dd, J = 7.9, 1.5 Hz, 1H), 7.54 (d, J =8.0 Hz, 1H), 7.45 (s, 1H), 6.89 (s, 2H), 6.44 (s, 1H), 5.22-5.11 (m,1H), 4.48 (d, J = 3.2 Hz, 2H), 4.22 (s, 2H), 4.16- 1.09 (m, 2H), 3.96(s, 6H), 3.87 (s, 2H), 3.73-3.63 (ms, 1H), 3.60 (s, 3H), 3.08 (s, 6H),3.01-2.88 (m, 1H), 2.86-2.77 (m, 1H), 2.58- 2.44 (m, 1H), 2.28-2.19 (m,1H). D268 694.35 ¹H NMR (400 MHz, Methanol-d4) δ 9.15 (d, J = 0.8 Hz,1H), 8.48 (s, 0.2H, FA), 7.73 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.19(d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.5, 2.4 Hz, 1H), 6.90-6.83 (m, 2H),6.48 (s, 1H), 5.10 (dd, J = 12.5, 5.4 Hz, 1H), 4.38-4.17 (m, 4H), 4.08-3.77 (m, 8H), 3.67-3.54 (m, 3H), 3.22-2.96 (m, 9H), 2.95-2.67 (m, 4H),2.16-2.07 (m, 1H). D269 700.35 ¹H NMR (300 MHz, DMSO-d6) δ 11.01 (s,1H), 9.28 (s, 1H), 7.80 (s, 1H), 7.71-7.53 (m, 3H), 7.42 (s, 1H), 6.78(s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.54-4.27 (m, 2H), 3.86 (s,6H), 3.79-3.67 (m, 2H), 3.56 (s, 3H), 3.02-2.82 (m, 3H), 2.81-2.66 (m,1H), 2.66- 2.53 (m, 1H), 2.47-2.16 (m, 4H), 2.08-1.83 (m, 3H), 1.80-1.57 (m, 2H), 1.09-0.89 (m, 4H). D270 615.25 ¹H NMR (300 MHz,Methanol-d4) δ 9.05 (d, J = 1.4 Hz, 2H), 7.57 (d, J = 1.4 Hz, 1H), 7.47(d, J = 1.0 Hz, 1H), 7.41 (d, J = 0.9 Hz, 1H), 6.92 (s, 2H), 6.68 (d, J= 2.3 Hz, 1H), 5.22 (dd, J = 12.0, 5.1 Hz, 1H), 4.50 (s, 2H), 3.99 (s,6H), 3.69-3.50 (m, 7H), 3.50-3.38 (m, 2H), 3.20 (s, 6H), 3.13-2.99 (m,2H), 2.90-2.79 (m, 2H), 2.73- 2.55 (m, 1H), 2.42-2.29 (m, 1H). D271672.35 ¹H NMR (400 MHz, Methanol-d4) δ 9.35 (s, 1H), 8.53 (s, 1H, FA),7.76 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 2.0 Hz, 2H), 7.60-7.53 (m, 1H),7.33 (d, J = 0.9 Hz, 1H), 6.81 (s, 2H), 5.19-5.10 (m, 1H), 4.53- 4.38(m, 2H), 4.20 (s, 2H), 4.10 (t, J = 8.4 Hz, 2H), 3.93 (s, 6H), 3.89-3.81(m, 2H), 3.77-3.67 (m, 1H), 3.64 (s, 3H), 2.98-2.84 (m, 1H), 2.84-2.73(m, 1H), 2.55-2.40 (m, 1H), 2.22-2.13 (m, 1H), 2.13-2.03 (m, 1H), (d, J= 6.5 Hz, 4H). D272 714.30 ¹H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H),9.28 (s, 1H), 7.94- 7.78 (m, 4H), 7.41 (s, 1H), 6.81 (s, 2H), 5.16 (dd,J = 12.8, 5.4 Hz, 1H), 3.87 (s, 8H), 3.57 (s, 4H), 3.02 (s, 2H),2.96-2.78 (m, 3H), 2.67-2.55 (m, 2H), 2.21 (dd, J = 9.0, 4.1 Hz, 1H),2.11-1.95 (m, 3H), 1.79 (s, 2H), 1.05-0.94 (m, 4H). D273 717.20 ¹H NMR(300 MHz, Methanol-d4) δ 9.10 (dd, J = 9.6, 0.7 Hz, 1H), 7.93-7.80 (m,3H), 7.49 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 7.2 Hz, 2H), 6.57 (s, 1H),5.14 (ddd, J = 17.9, 12.7, 5.5 Hz, 1H), 4.52 (s, 1H), 4.44 (s, 1H), 4.00(d, J = 2.0 Hz, 6H), 3.60 (d, J = 2.2 Hz, 5H), 3.51-3.40 (m, 1H),3.31-3.18 (m, 2H), 3.16 (s, 3H), 3.07 (s, 3H), 2.93-2.63 (m, 3H), 2.37(d, J = 13.9 Hz, 1H), 2.25-1.93 (m, 4H). D274 582.30 ¹H NMR (400 MHz,DMSO-d6) δ 11.01 (s, 1H), 9.05 (s, 1H), 7.68- 7.57 (m, 3H), 7.57-7.50(m, 1H), 6.89 (s, 2H), 6.59 (s, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H),4.51 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 3.74 (s, 6H), 3.50(s, 3H), 3.10 (s, 6H), 3.01-2.87 (m, 1H), 2.67-2.58 (m, 1H), 2.48-2.37(m, 1H), 2.10-2.00 (m, 1H). D275 686.20 ¹H NMR (300 MHz, DMSO-d6) δ11.16 (s, 1H), 10.15 (d, 1H, TFA), 9.29 (d, J = 4.1 Hz, 1H), 7.96 (d, J= 7.3 Hz, 3H), 7.81 (s, 1H), 7.38 (d, J = 11.7 Hz, 1H), 6.88 (d, J = 3.5Hz, 2H), 5.17 (dd, J = 12.8, 5.3 Hz, 1H), 4.48 (s, 4H), 4.22 (d, J =41.8 Hz, 2H), 3.92 (s, 6H), 3.57 (d, J = 1.9 Hz, 3H), 2.88 (d, J = 11.7Hz, 1H), 2.71-2.54 (m, 2H), 2.32-2.02 (m, 3H), 0.99 (d, J = 8.2 Hz, 4H).D276 711.20 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.03 (s, 1H),7.59 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.5, 2.4 Hz, 1H),7.13 (d, J = 2.3 Hz, 1H), 6.75 (s, 2H), 6.49 (s, 1H), 5.09 (dd, J =13.3, 5.1 Hz, 1H), 4.37-4.15 (m, 2H), 3.91 (d, J = 12.1 Hz, 1H), 3.83(s, 6H), 3.53 (d, J = 12.9 Hz, 1H), 3.15 (d, J = 10.9 Hz, 2H), 3.07 (s,6H), 3.04-2.98 (m, 2H), 2.96-2.84 (m, 3H), 2.69-2.54 (m, 1H), 2.45- 2.30(m, 1H), 2.04-1.92 (m, 1H), 1.22 (d, J = 6.1 Hz, 6H). D277 625.20 ¹H NMR(300 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.03 (s, 1H), 7.58 (s, 1H), 7.47 (d,J = 8.5 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.79 (s, 2H), 6.45 (s, 1H),5.03 (dd, J = 13.3, 5.2 Hz, 1H), 4.58 (s, 2H), 4.35- 4.15 (m, 2H), 3.85(s, 6H), 3.46 (s, 3H), 3.06 (s, 6H), 2.98 (s, 3H), 2.92-2.80 (m, 1H),2.66-2.55 (m, 1H), 2.41-2.32 (m, 1H), 2.02- 1.90(m, 1H). D278 756.35 ¹HNMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.10 (s, 1H), 7.69 (s, 1H), 7.41(d, J = 8.4 Hz, 1H), 7.31-7.18 (m, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.75(s, 2H), 6.49 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (t, J =12.3 Hz, 4H), 4.41-4.12 (m, 2H), 3.83 (s, 6H), 3.58 (s, 2H), 3.51 (s,3H), 3.02 (d, J = 23.7 Hz, 5H), 2.63 (s, 3H), 2.46-2.24 (m, 1H),2.10-1.91 (m, 1H), 1.25 (s, 6H). D279 694.40 ¹H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 8.99 (s, 1H), 8.13 (s, 0.2H, FA), 7.45-7.38 (m, 2H), 7.28(dd, J = 8.6, 2.5 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.83 (s, 1H), 6.72(s, 1H), 5.97 (s, 1H), 5.20-5.03 (m, 1H), 4.41-4.15 (m, 2H), 3.85 (d, J= 11.8 Hz, 2H), 3.76 (s, 3H), 3.66 (s, 3H), 3.51 (s, 1H), 3.44 (s, 3H),3.01 (s, 6H), 5.23-4.94 (m, 1H), 2.82-2.68 (m, 5H), 2.65-2.55 (m, 1H),2.45- 2.30 (m, 1H), 7.31-7.25 (m, 1H), 1.81 (s, 4H). D280 679.30 ¹H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.02 (s, 1H), 7.58 (s, 1H),7.55-7.51 (m, 1H), 7.47 (s, 2H), 6.76 (s, 2H), 6.51 (s, 1H), 5.10 (dd, J= 13.3, 5.1 Hz, 1H), 4.39 (d, J = 17.1 Hz, 1H), 4.26 (d, J = 17.1 Hz,1H), 3.83 (s, 6H), 3.70 (d, J = 11.9 Hz, 2H), 3.48 (s, 3H), 3.08 (s,6H), 3.03-2.83 (m, 3H), 2.65-2.56 (m, 3H), 2.47-2.32 (m, 1H), 2.06-1.94(m, 1H), 1.82 (s, 1H), 1.72 (d, J = 12.8 Hz, 2H), 1.54-1.47 (m, 2H).D281 695.50 ¹H NMR (400 MHz, Methanol-d4) δ 9.27 (s, 1H), 7.59 (s, 1H),7.53 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 9.7 Hz, 2H), 6.89 (s, 2H), 6.83(s, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.63 (d, J = 20.8 Hz, 1H),4.57- 4.38 (m, 3H), 4.01 (d, J = 5.1 Hz, 10H), 3.96-3.85 (m, 3H), 3.65(s, 3H), 3.60-3.44 (m, 1H), 2.99-2.87 (m, 1H), 2.86-2.75 (m, 1H),2.59-2.45 (m, 1H), 2.25-2.13 (m, 1H), 1.74-1.51 (m, 7H). D282 628.40 ¹HNMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.16 (s, 1H), 8.14 (0.4 H, FA),7.74 (s, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.79-6.72 (m, 3H), 6.56-6.49 (m,2H), 6.46-6.40 (m, 1H), 5.18 (dd, J = 10.5, 5.2 Hz, 1H), 3.94 (s, 3H),3.82 (s, 6H), 3.64 (s, 2H), 3.54 (s, 3H), 3.15-3.04 (m, 4H), 2.75-2.55(m, 6H), 2.24-2.02 (m, 2H). D283 845.3 ¹H NMR (300 MHz, Methanol-d4) δ9.04 (s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.24-7.13 (m, 2H),6.81 (s, 2H), 5.18 (d, J = 5.1 Hz, 1H), 4.67 (s, 2H), 4.44 (d, J = 5.3Hz, 4H), 3.95 (s, 6H), 3.68 (s, 5H), 3.58 (s, 4H), 3.43 (s, 1H), 3.22(m, J = 12.3 Hz, 2H), 3.10 (d, J = 6.6 Hz, 3H), 3.03 (s, 1H), 2.98-2.85(m, 2H), 2.83 (s, 1H), 2.52 (m, J = 12.9, 4.9 Hz, 2H), 2.32 (s, 3H),2.21 (s, 1H), 2.10 (d, J = 14.3 Hz, 8H), 1.74 (t, J = 12.9 Hz, 2H). D284843.4 ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (d, J = 9.0 Hz, 1H), 7.49 (d,J = 8.3 Hz, 1H), 7.28-7.07 (m, 3H), 6.84-6.67 (m, 3H), 6.11 (d, J = 7.6Hz, 1H), 5.15 (dd, J = 13.2, 5.2 Hz, 1H), 4.85-4.77 (m, 1H), 4.55-4.34(m, 4H), 3.92 (s, 6H), 3.70 (t, J = 7.3 Hz, 4H), 3.61- 3.48 (m, 5H),3.22-3.04 (m, 2H), 2.97-2.44 (m, 11H), 2.27-1.75 (m, 12H), 1.74-1.42 (m,2H). D285 788.6 ¹H NMR (400 MHz, MeOD) δ 8.85-8.50 (m, FA, 1H), 8.31 (d,J = 9.0 Hz, 1H), 7.37 (dd, J = 18.8, 8.6 Hz, 2H), 7.18 (d, J = 7.8 Hz,1H), 6.85 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.2, 2.2 Hz, 1H), 6.75 (s,2H), 6.32 (d, J = 7.7 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 (s,2H), 4.45-4.33 (m, 2H), 4.31-4.22 (m, 2H), 4.06-3.95 (m, 2H), 3.93 (s,6H), 3.68 (s, 4H), 3.58 (s, 3H), 3.22-3.13 (m, 1H), 2.99-2.85 (m, 1H),2.85-2.72 (m, 3H), 2.70 (s, 6H), 2.60-2.43 (m, 5H), 2.23-2.11 (m, 1H),1.96-1.88 (m, 4H). D286 845.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H),9.35 (s, 1H), 9.14 (s, 1H), 8.11 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H),7.20-7.11 (m, 4H), 5.13-5.07 (m, 1H), 4.90-4.85 (m, 1H), 4.38 (d, J =17.0 Hz, 1H), 4.34-4.07 (m, 7H), 3.91 (s, 6H), 3.54 (s, 3H), 3.19 (s,2H), 2.97- 2.76 (m, 7H), 2.60 (d, J = 15.7 Hz, 2H), 2.40-2.27 (m, 5H),2.02- 1.83 (m, 11H), 1.50 (q, J = 12.2 Hz, 2H). D287 806 ¹H NMR (300MHz, DMSO-d6) δ 11.00 (s, 1H), 8.01 (dd, J = 9.5, 2.8 Hz, 1H), 7.74 (m,J = 9.1, 5.3 Hz, 1H), 7.68-7.57 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H),7.20-7.02 (m, 2H), 6.82 (s, 2H), 5.11 (m, J = 13.2, 5.1 Hz, 1H),4.93-4.75 (m, 1H), 4.35 (m, 1H), 4.26 (m, 1H), 4.10 (m, 1H), 3.87 (s,6H), 3.61 (s, 3H), 3.29 (s, 2H), 3.01-2.81 (m, 3H), 2.78-2.56 (m, 2H),2.49-2.25 (m, 7H), 2.10-1.93 (m, 1H), 1.73 (m, J = 48.1 Hz, 10H),1.43-1.22 (m, 3H). D288 666.25 ¹H NMR (300 MHz, Methanol-d4) δ 9.25 (s,1H), 8.56 (d, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H),7.48 (d, J = 8.1 Hz, 1H), 6.94-6.78 (m, 3H), 5.17 (dd, J = 13.3, 5.1 Hz,1H), 4.51 (d, J = 5.0 Hz, 2H), 4.37-4.24 (m, 2H), 4.01 (s, 3H), 3.97 (s,6H), 3.65 (s, 3H), 3.57 (d, J = 12.0 Hz, 2H), 3.16-2.97 (m, 3H),2.97-2.86 (m, 1H), 2.86-2.75 (m, 1H), 2.51 (qd, J = 13.1, 4.7 Hz, 1H),2.27- 2.15 (m, 1H), 2.15-2.03 (m, 4H). D289 804.45 ¹H NMR (400 MHz,DMSO-d6) δ 10.97 (s, 1H), 9.17 (s, 1H), 7.73 (s, 1H), 7.38 (d, J = 8.0Hz, 1H), 6.79 (d, J = 5.4 Hz, 3H), 6.69 (d, J = 8.0 Hz, 2H), 5.08 (dd, J= 13.2, 5.2 Hz, 1H), 4.36-4.12 (m, 2H), 3.94 (s, 3H), 3.90 (s, 2H), 3.85(s, 6H), 3.59 (s, 4H), 3.55 (s, 3H), 3.19-3.15 (m, 2H), 2.96-2.84 (m,1H), 2.70-2.60 (m, 2H), 2.42- 2.33 (m, 2H), 2.37 (s, 4H), 2.17 (s, 2H),1.99 (d, J = 12.8 Hz, 1H), 1.82-1.67 (m, 7H), 1.42-1.07 (m, 2H). D290720.40 ¹H NMR (300 MHz, Methanol-d4) δ 9.10 (s, 1H), 8.51 (s, 0.2H, FA),7.46 (d, J = 11.0 Hz, 2H), 7.31 (d, J = 9.3 Hz, 2H), 6.80 (s, 2H), 6.23(s, 1H), 5.21-5.09 (m, 1H), 4.51-4.33 (m, 2H), 4.14-4.03 (m, 4H), 3.93(s, 8H), 3.59 (s, 3H), 3.20-3.14 (m, 5H), 2.96-2.70 (m, 3H), 2.56-2.37(m, 3H), 2.24-2.13 (m, 1H), 1.49 (s, 6H). D291 865.50 ¹H NMR (400 MHz,DMSO-d6) δ 10.98 (s, 1H), 9.46 (d, J = 40.5 Hz, 1H, TFA), 9.11 (s, 1H),7.69 (s, 1H), 7.45-7.38 (m, 1H), 6.90 (s, 2H), 6.74-6.67 (m, 2H), 6.49(s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (t, J = 12.3 Hz, 4H),4.33 (d, J = 16.6 Hz, 1H), 4.26-4.16 (m, 3H), 3.91 (s, 6H), 3.71 (dd, J= 30.9, 7.8 Hz, 4H), 3.53 (s, 3H), 3.47 (d, J = 12.9 Hz, 3H), 3.22 (s,1H), 3.01 (s, 6H), 2.60 (d, J = 17.1 Hz, 1H), 2.39 (dd, J = 13.1, 4.5Hz, 1H), 2.37-2.30 (m, 1H), 2.12 (d, J = 12.9 Hz, 3H), 1.97 (t, J = 16.1Hz, 5H), 1.83 (s, 0H), 1.59-1.48 (m, 2H). D292 875.3 ¹H NMR (400 MHz,DMSO-d6) δ 10.99 (s, 1H), 9.41 (s, 1H), 8.18 (s, 2H, FA), 7.87 (s, 1H),7.56 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.13 (dd, J = 8.3, 2.4 Hz, 1H),7.07 (d, J = 2.4 Hz, 1H), 6.77 (s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H),4.84 (t, J = 6.9 Hz, 1H), 4.42-4.19 (m, 2H), 3.83 (s, 7H), 3.67 (s, 2H),3.60 (s, 3H), 3.51 (s, 3H), 3.11 (s, 3H), 2.97-2.88 (m, 3H), 2.60 (d, J= 17.2 Hz, 1H), 2.41-2.27 (m, 4H), 2.21 (d, J = 14.0 Hz, 3H), 2.10 (d, J= 7.0 Hz, 2H), 2.00 (d, J = 12.9 Hz, 1H), 1.78 (s, 2H), 1.60 (d, J =27.7 Hz, 6H), 1.49 (s, 1H), 1.29 (s, 6H), 1.12 (t, J = 12.9 Hz, 2H).D293 681.40 ¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.16 (s, 1H),7.74 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.32-7.21 (m, 1H), 7.16 (d, J =2.3 Hz, 1H), 6.78 (s, 1H), 6.74 (s, 2H), 5.10 (dd, J = 13.2, 5.0 Hz,1H), 4.40-4.13 (m, 2H), 4.09-3.98 (m, 1H), 3.94 (s, 3H), 3.83 (s, 6H),3.64-3.46 (m, 5H), 3.00-2.68 (m, 4H), 2.67-2.53 (m, 3H), 2.46-2.25 (m,2H), 2.07-1.90 (m, 1H), 1.30 (d, J = 5.0 Hz, 3H). D294 677.45 ¹H NMR(400 MHz, Methanol-d4) δ 8.91 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.85(dd, J = 8.3, 2.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 6.75(s, 2H), 6.43 (s, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.63- 4.47 (m,2H), 4.24 (t, J = 7.6 Hz, 4H), 3.89 (s, 6H), 3.87-3.73 (m, 3H), 3.63 (t,J = 12.1 Hz, 2H), 3.57 (s, 3H), 2.99-2.74 (m, 4H), 2.60-2.44 (m, 3H),2.21 (ddd, J = 9.7, 5.3, 2.7 Hz, 1H), 1.86 (d, J = 13.8 Hz, 2H). D295652.40 ¹H NMR (400 MHz, Methanol-d4) δ 9.23 (s, 1H), 8.09 (d, J = 2.2Hz, 1H), 7.97 (dd, J = 8.3, 2.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.51(s, 1H), 6.80 (s, 1H), 6.74 (s, 2H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H),4.67- 4.49 (m, 2H), 3.99 (s, 3H), 3.90 (s, 6H), 3.88-3.76 (m, 5H), 3.62(s, 3H), 3.03-2.86 (m, 3H), 2.80 (ddd, J = 17.5, 4.8, 2.4 Hz, 1H), 2.53(qd, J = 13.2, 4.7 Hz, 1H), 2.21 (ddd, J = 10.9, 5.4, 3.0 Hz, 1H), 1.95(d, J = 13.5 Hz, 2H).

Example 45—Preparation of4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde

Step 1: Preparation of 6-chloro-4-methylpyridine-3-carboxamide

To a stirred mixture of 6-chloro-4-methylpyridine-3-carboxylic acid(20.00 g, 116.564 mmol, 1.00 equivalent) and NH₄Cl (62.35 g, 1.17 mol,10.00 equivalent) in DCM (400 mL) was added DIEA (22.60 g, 174.846 mmol,3.00 equivalent). After stirring for 5 min, HATU (66.48 g, 174.846 mmol,1.50 equivalent) was added in portions. The resulting mixture wasstirred for 3 hours at room temperature. The resulting mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography, eluted with PE/EtOAc from 1/1 to 3/2to afford 6-chloro-4-methylpyridine-3-carboxamide (18.30 g, 61.3%) as ayellow solid. LCMS (ESI) m/z: [M+H]⁺=171.

Step 2: Preparation of6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide

To a stirred mixture of 6-chloro-4-methylpyridine-3-carboxamide (18.30g, 107.268 mmol, 1.00 equivalent) and in 2-methyltetrahydrofuran (100mL) was added DMF-DMA (19.17 g, 160.903 mmol, 1.50 equivalent) at 80° C.under nitrogen atmosphere and stirred for additional 1 hour. Then themixture was cooled and concentrated to afford6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide(26.3 g, 91.3%) as a yellow crude solid, that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]⁺=226.

Step 3: Preparation of 6-chloro-2H-2,7-naphthyridin-1-one

To a stirred mixture of6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide(26.30 g) in THF (170.00 mL) was added t-BuOK (174.00 mL, 1 mol/L inTHF), the resulting solution was stirred at 60° C. under nitrogenatmosphere for 30 min. Then the mixture was cooled and concentratedunder reduced pressure, the crude solid was washed with saturated NaHCO₃solution (100 mL) and collected to give6-chloro-2H-2,7-naphthyridin-1-one (14.1 g, 67.0%) as a pink solid, thatwas used directly without further purification. LCMS (ESI) m/z:[M+H]⁺=181.

Step 4: Preparation of 6-chloro-2-methyl-2,7-naphthyridin-1-one

To a stirred mixture of 6-chloro-2H-2, 7-naphthyridin-1-one (14.10 g,78.077 mmol, 1.00 equivalent) in anhydrous THF (280.00 mL) was added NaH(9.37 g, 234.232 mmol, 3.00 equivalent, 60%) in portions at 0° C. After10 min, to above mixture was added Mel (33.25 g, 234.232 mmol, 3.00equivalent) at 0° C., the mixture was allowed to stir for 10 min at 0degrees. Then the mixture was allowed to stir for 12 h at roomtemperature. The resulting mixture was concentrated under reducedpressure. The crude solid was slurried with water (100 mL), and thesolid was filtered and collected to give the6-chloro-2-methyl-2,7-naphthyridin-1-one (14.6 g, 94.1%) as a yellowsolid, that was used directly without further purification. LCMS (ESI)m/z: [M+H]⁺=195.

Step 5: Preparation of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one

To a stirred mixture of 6-chloro-2-methyl-2,7-naphthyridin-1-one (8.00g, 41.106 mmol, 1.00 equivalent) in DMF (160.00 mL) was added NBS (8.78g, 49.327 mmol, 1.20 equivalent), the resulting mixture was stirred for2 h at 90° C. The reaction mixture was cooled and diluted with DCM (150mL), and washed with water (3×100 mL), the organic layers were dried andconcentrated. Then the residue was slurried with EtOAc (20 mL), theslurry was filtered, the filter cake was washed with EtOAc (20 mL) togive 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (6.32 g, 55.7%) asa white solid, that was used directly without further purification. LCMS(ESI) m/z: [M+H]⁺=273.

Step 6: Preparation of4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one

A stirred mixture of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one(6.00 g, 21.937 mmol, 1.00 equivalent), dimethylamine hydrochloride(5.37 g, 65.811 mmol, 3.00 equivalent) and K₂CO₃ (15.16 g, 109.685 mmol,5.00 equivalent) in DMSO (60.00 mL) was heated at 130° C. under nitrogenatmosphere. After 3 h, the resulting mixture was cooled and diluted withwater (100 mL), and then extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with saturated NaCl solution (3×50 mL), driedover anhydrous Na₂SO₄, concentrated under reduced pressure to afford4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one (5.91 g,93.6%) as a yellow solid, that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=282.

Step 7: Preparation of(4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

To a stirred mixture of4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one (5.70 g,20.203 mmol, 1.00 equivalent) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(8.26 g, 28.284 mmol, 1.40 equivalent) in dioxane (100.00 mL) and H₂O(10.00 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (1.65 g, 2.020 mmol, 0.10equivalent) and 052003 (13.16 g, 40.405 mmol, 2.00 equivalent), then themixture was allowed to stir for 4 h at 70° C. under nitrogen atmosphere.The resulting mixture was cooled and concentrated under reducedpressure, the residue was slurried with water (100 mL) and filtered, thefilter cake was collected. And this solid was further slurried with MeOH(100 mL) and filtered, the solid was collected to afford product toafford4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(6.10 g, 77.6%) as a brown solid. LCMS (ESI) m/z: [M+H]⁺=368.

Example 46—Preparation of3-(6-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneformic acid; and3-(5-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneformic acid

Step 1: Preparation of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a stirred solution of 5-bromo-2-benzofuran-1,3-dione (10.00 g, 44.050mmol, 1.00 equivalent), NaOAc (7.23 mg, 88.134 mmol, 2.00 equivalent)and 3-aminopiperidine-2,6-dione (11.29 g, 88.113 mmol, 2.00 equivalent)in AcOH (80.00 mL) at room temperature. The resulting mixture wasstirred for 16 h at 115° C. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with petroleum ether/EtOAc (10:1) to afford5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (13.6 g, 91.6%)as a dark brown solid. LCMS (ESI) m/z: [M+H]⁺=337.

Step 2: Preparation of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

To a stirred solution of5-bromo-2-(2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (3.00 g, 8.899mmol, 1.00 equivalent), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(3.30 g, 10.672 mmol, 1.20 equivalent), K₃PO₄ (5.67 g, 26.712 mmol, 3.00equivalent) in dioxane (20.00 mL) and H₂O (4.00 mL) was addedPd(PPh₃)₂Cl₂ (0.62 g, 0.883 mmol, 0.10 equivalent) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 16 h at80° C. under nitrogen atmosphere. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (8/1) to afford tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(0.8 g, 20.5%) as a colorless oil. LCMS (ESI) m/z: [M+H]⁺=440.

Step 3: Preparation of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(0.80 g) in THF (20.00 mL) was added 10% Pd/C (500.0 mg) under nitrogenatmosphere in a 100 mL round-bottom flask. The mixture was hydrogenatedat room temperature for 12 h under hydrogen atmosphere using a hydrogenballoon, filtered through a Celite pad and concentrated under reducedpressure. This resulted in tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate(0.73 g, crude) as a white solid that was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=442.

Step 4: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1-carboxylate;tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate(0.73 g, 16.55 mmol, 1.00 equivalent) and Zn (1.08 g, 1.65 mmol, 10.00equivalent) in AcOH (10.00 mL) at room temperature. The resultingmixture was stirred for 2 h at 60° C. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (2:1) to affordtert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1-carboxylate;tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)piperidine-1-carboxylate(0.546 g, 74.8%, mixture of two regio-isomers) as a colorless solid.LCMS (ESI) m/z: [M+H]⁺=444.

Step 5: Preparation of3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione;3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione

To a stirred solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1-carboxylate;tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)piperidine-1-carboxylate(mixture of two regio-isomers, 573.00 mg, 1.00 equivalent) and TFA (3.00mL) in DCM (9.00 mL) was added TES (450.7 mg, 3.876 mmol, 3.00equivalent) at room temperature. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was concentrated underreduced pressure, This was used directly without further purification,to afford3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione;3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (200 mg36.6% mixture of two regio-isomers) as an off-white oil. LCMS (ESI) m/z:[M+H]⁺=328.

Step 6: Preparation of3-(6-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneformic acid; and3-(5-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneformic acid

To a stirred solution of3-[1-oxo-6-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (165.0mg, 0.504 mmol, 1.00 equivalent), and3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione;3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (mixtureof two regio-isomers, 222.2 mg, 0.605 mmol, 1.20 equivalent) in DMF(4.00 mL) was added NaBH(OAc)₃ (427.3 mg, 2.016 mmol, 4.00 equivalent)at room temperature. The resulting mixture was stirred for 16 h at roomtemperature. The residue was purified by reverse flash chromatographywith the following conditions: column, C18 silica gel; mobile phase,CH₃CN in water (0.05% FA), 0% to 50% gradient in 30 min; detector, UV254 nm. The crude product was purified by Prep-HPLC with the followingconditions: Column, Sunfire Prep C18 OBD Column, 10 μm, 19*250 mm;mobile phase, water (0.05% FA) and CH₃CN (15% to 22% CH₃CN in 15 min);Detector, UV 254 nm. This resulted in3-[6-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid (52.5 mg, 26.3%) as a white solid and3-[5-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid (68.4 mg, 34.2%) as a yellow solid.

For3-[6-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.04 (s, 1H),8.20 (s, 1H, FA), 7.58 (d, J=14.5 Hz, 2H), 7.52 (s, 2H), 6.79 (s, 2H),6.50 (s, 1H), 5.10 (dd, J=13.4, 5.1 Hz, 1H), 4.41 (d, J=17.1 Hz, 1H),4.28 (d, J=17.0 Hz, 1H), 3.84 (s, 6H), 3.68 (s, 2H), 3.49 (s, 3H),3.08-3.05 (m, 8H), 2.91-2.89 (m, 1H), 2.66-2.56 (m, 2H), 2.40-2.35 (m,1H), 2.30 (t, J=11.3 Hz, 2H), 2.03-1.95 (m, 1H), 1.88-1.57 (m, 4H). LCMS(ESI) m/z: [M+H]⁺=679.32.

For3-[5-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.05 (s, 1H),8.15 (s, 1H, FA), 7.69 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H),7.40 (d, J=7.9 Hz, 1H), 6.87 (s, 2H), 6.51 (s, 1H), 5.11 (dd, J=13.3,5.1 Hz, 1H), 4.44 (d, J=17.3 Hz, 1H), 4.31 (d, J=17.3 Hz, 1H), 4.05 (s,2H), 3.90 (s, 6H), 3.49 (s, 3H), 3.31 (d, J=11.7 Hz, 2H), 3.09 (s, 6H),2.99-2.71 (m, 4H), 2.65-2.56 (m, 1H), 2.47-2.33 (m, 1H), 2.04-1.96 (m,1H), 1.92 (m, 4H). LCMS (ESI) m/z: [M+H]⁺=679.32.

Example 47—Preparation of3-[6-[(7-[[1-(2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]ethyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dionebis(trifluoroacetic acid)

Step 1: Preparation of tert-butyl2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (1.37 g, 4.996mmol, 1.00 equivalent) and tert-butyl2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.81 g, 7.494 mmol, 1.5equivalent) in THF (30.00 mL) was added PPh₃ (1.97 g, 7.494 mmol, 1.5equivalent). To the above mixture was added DIAD (1.52 g, 7.494 mmol,1.5 equivalent) dropwise over 10 min at 0° C. The resulting mixture wasstirred for additional 5 h at room temperature. The resulting mixturewas concentrated under reduced pressure. The residue was purified byreverse flash chromatography with the following conditions: column, C18silica gel; mobile phase, FA in water, 0% to 100% gradient in 45 min;detector, UV 254 nm. This resulted in tert-butyl2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate(1.964 g, 79.0%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=498.

Step 2: Preparation of5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid

To a solution of tert-butyl2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonane-7-carboxylate(1.96 g, 3.939 mmol) in DCM (10.00 mL) was added TFA (10.00 mL). Theresulting mixture was stirred for 5 h at room temperature. The reactionmixture was concentrated in vacuo to give crude5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid, which was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=398.

Step 3: Preparation of tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate

To a solution of5-[7-azaspiro[3.5]nonan-2-yloxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(2.65 g, 6.668 mmol, 1.00 equivalent) and tert-butyl4-formylpiperidine-1-carboxylate (1.42 g, 6.668 mmol, 1 equivalent) inDMF (30.00 mL) was added NaBH(OAc)₃ (4.24 g, 20.003 mmol, 3 equivalent)at room temperature. The resulting mixture was stirred for 3 h at roomtemperature. The reaction was quenched by the addition of water (100 mL)at room temperature. The resulting mixture was extracted with EtOAc(3×150 mL). The combined organic layers were washed with brine (3×150mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. This resulted in tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate(3.11 g, 78.4%) as a light yellow solid; LCMS (ESI) m/z: [M+H]⁺=595.

Step 4: Preparation of tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylateand tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate(3.00 g, 5.044 mmol, 1.00 equivalent) in AcOH (60.00 mL) were added Zn(3.30 g, 50.445 mmol, 10 equivalent) at room temperature. The resultingmixture was stirred for 3 h at 60° C. The resulting mixture wasfiltered, and the filter cake was washed with MeCN (3×100 mL). Thefiltrate was concentrated under reduced pressure. The residue waspurified by reverse flash chromatography with the following conditions:column, C18 silica gel; mobile phase, FA in water, 0% to 100% gradientin 35 min; detector, UV 254 nm. This resulted in the mixture oftert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylateand tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate(mixture, 1.6 g, 53.2%) a light yellow solid. LCMS (ESI) m/z:[M+H]⁺=597.

Step 5: Preparation of3-(1-oxo-6-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dioneand3-(1-oxo-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione

To a solution of the mixture of tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate(2.40 g, 4.022 mmol, 1.00 equivalent) and tert-butyl4-[(2-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]-7-azaspiro[3.5]nonan-7-yl)methyl]piperidine-1-carboxylate)in DCM (50.00 mL) were added TFA (5.00 mL, 67.315 mmol, 16.74equivalent) and Et₃SiH (4.68 g, 40.220 mmol, 10 equivalent) at roomtemperature. The resulting mixture was stirred for 12 h at roomtemperature. The resulting mixture was concentrated under reducedpressure. The residue was purified by reverse flash chromatography withthe following conditions: column, C18 silica gel; mobile phase, TFA inwater, 0% to 10% gradient in 45 min; detector, UV 254 nm. This resultedin3-(1-oxo-6-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione(600 mg, 31.0%) and3-(1-oxo-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione(1.2 g, 62.1%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=481.

Step 6:2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]acetaldehyde

To a stirred mixture of4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(150.0 mg, 0.408 mmol, 1.00 equivalent) and(methoxymethyl)triphenylphosphanium chloride (559.8 mg, 1.633 mmol, 4equivalent) in THF (5.0 mL) was added t-BuOK (183.2 mg, 1.633 mmol, 4equivalent). The resulting mixture was stirred for 30 min at roomtemperature under nitrogen atmosphere. To the above mixture was addedHCl (6M, 0.5 mL, 0.30 mmol) dropwise. The resulting mixture was stirredfor additional 30 min at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by reverse phasecolumn with the following conditions: column, C18 silica gel; mobilephase, ACN in water, 10% to 80% gradient in 15 min; detector, UV 254 nm.This resulted in2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]acetaldehyde(160 mg, 95.1%) as a white solid. LCMS (ESI) m/z: [M+H]+=382.

Step 7:3-[6-[(7-[[1-(2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]ethyl)piperidin-4-yl]ethyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dionebis(trifluoroacetic acid)

To a stirred solution of2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]acetaldehyde(150.0 mg, 0.393 mmol, 1.00 equivalent) and3-(1-oxo-6-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione(189.0 mg, 0.393 mmol, 1 equivalent) in DMF (2.0 mL) was addedNaBH(OAc)₃ (250.0 mg, 1.180 mmol, 3 equivalent). The resulting mixturewas stirred for 2 h at room temperature under nitrogen atmosphere. Thecrude reaction mixture was purified by Prep-HPLC with the followingconditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm;Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25mL/min; Gradient: 8 B to 25 B in 15 min; 254/220 nm; RT1: 12.28 min) toafford3-[6-[(7-[[1-(2-[4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]ethyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;bis(trifluoroacetic acid) (101.2 mg, 30.4%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.49 (d, J=109.5 Hz, 2H, TFA salt),9.04 (s, 1H), 7.57-7.48 (m, 2H), 7.18-7.09 (m, 2H), 6.81 (d, J=2.8 Hz,2H), 6.48 (s, 1H), 5.11 (dd, J=13.1, 5.2 Hz, 1H), 4.89 (p, J=6.8 Hz,1H), 4.38 (d, J=17.0 Hz, 1H), 4.28-4.22 (m, 2H), 3.85 (s, 6H), 3.68 (d,J=11.3 Hz, 2H), 3.48 (s, 3H), 3.40 (d, J=11.9 Hz, 1H), 3.33-3.18 (m,1H), 3.08 (s, 6H), 3.06-2.84 (m, 9H), 2.65-2.56 (m, 2H), 2.46-2.36 (m,2H), 2.14-1.93 (m, 6H), 1.92-1.79 (m, 5H), 1.46 (q, J=12.2 Hz, 2H). LCMS(ESI) m/z: [M+H]+=846.25.

Example 48—Preparation4-(6-cyclopropyl-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde

Step 1: Preparation of 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one

To a stirred solution of 6-chloro-2-methyl-2,7-naphthyridin-1-one(500.00 mg, 2.569 mmol, 1.00 equivalent) and cyclopropylboronic acid(441.37 mg, 5.138 mmol, 2 equivalent) in toluene (20.00 mL) and water(1.00 mL) was added tricyclohexylphosphane (144.09 mg, 0.514 mmol, 0.20equivalent), Pd(AcO)₂ (57.68 mg, 0.257 mmol, 0.10 equivalent) and K₃PO₄(1636.01 mg, 7.707 mmol, 3.00 equivalent) at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 1 h at 110°C. The mixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(50:1) to afford 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (340 mg,59.48%) as a brown solid. LCMS (ESI) m/z: [M+H]+=201.

Step 2: Preparation of4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one

To a stirred solution of 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one(100.00 mg, 0.499 mmol, 1.00 equivalent) in DMF (4.00 mL) was added NBS(106.66 mg, 0.599 mmol, 1.20 equivalent) at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C.The resulting mixture was diluted with water (12 mL), extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine(2×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure to afford4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (400 mg, 75.96%)as a brown solid. That was used directly without further purification.LCMS (ESI) m/z: [M+H]+=279.

Step 3: Preparation of4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde

To a stirred solution of4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (420.00 mg, 1.505mmol, 1.00 equivalent) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(527.48 mg, 1.806 mmol, 1.2 equivalent) in dioxane (10.00 mL) and water(2.00 mL) was added Pd(dppf)Cl₂ (110.09 mg, 0.150 mmol, 0.10 equivalent)and K₂CO₃ (415.90 mg, 3.009 mmol, 2.00 equivalent) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred forovernight at 80° C. The mixture was concentrated under reduced pressure.The residue was purified by Prep-TLC (CH2Cl2/MeOH 50:1) to afford4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(440 mg, 72.22%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=365.

Example 49—Preparation of5-[4-[2-(4-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperazin-1-yl)ethyl]piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

Step 1: Preparation of benzyl4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (4.02g, 17.709 mmol, 1.00 equivalent) and benzyl piperazine-1-carboxylate(3.90 g, 17.727 mmol, 1.00 equivalent) in MeOH (40 mL) was added NaBH₃CN(2.26 g, 35.313 mmol, 2 equivalent), the resulting solution was stirredat 25° C. for 1 hours. The resulting mixture was diluted with water (50mL), extracted with EA (30 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elutiongradient 0 to 45% THF in petroleum ether. Pure fractions were evaporatedto dryness to afford benzyl4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate(2.76 g, 35.71%) as a colorless oil. LCMS (ESI) m/z: [M+H]⁺=432.

Step 2: Preparation of benzyl4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate

To a solution of benzyl4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate(2.76 g, 6.403 mmol, 1.00 equivalent) in DCM (8.00 mL) was added asolution of HCl in 1,4-dioxane (8.00 mL, 4 mol/L), the resulting mixturewas stirred at 25° C. for 1 hour. The resulting mixture was filtered,the filter cake was washed with DCM (5 mL). The collected solid wasdried under reduced pressure to afford4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate (2.08 g, 98.11%) asa white solid. LCMS (ESI) m/z: [M+H]⁺=331.

Step 3: Preparation of benzyl4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazine-1-carboxylate

To a solution of 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate(1.50 g, 4.532 mmol, 1.00 equivalent) and2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.25 g, 4.532mmol, 1 equivalent) in DMSO (15.00 mL) was added DIEA (3.51 g, 27.192mmol, 6 equivalent), the resulting solution was stirred at 100° C. for 2hour. The reaction mixture was diluted with EA (500 mL).

The resulting mixture was washed with water (300 mL×3) and saturatedbrine (300 mL×1). The organic layer was dried over Na₂SO₄, filtered andevaporated to afford crude product. The crude product was purified bysilica gel column chromatography, elution gradient 0 to 100% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to affordbenzyl4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazine-1-carboxylate(1.44 g, 54.13%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=588.

Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperazin-1-yl)ethyl)piperidin-1-yl)isoindoline-1,3-dione

To a solution4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazine-1-carboxylate(1.04 g, 1.772 mmol, 1.00 equivalent) in DCM (30.00 mL) was added asolution of BBr₃ in DCM (20 mL, 1M), the resulting mixture was stirredat 0° C. for 1 hour. The reaction mixture was poured into ice-water (100mL), extracted with DCM (30 mL×3), the aqueous layer was concentratedunder reduced pressure. The residue was purified by flash C18-flashchromatography, elution gradient 0 to 50% MeCN in water (containing 0.1%HCl). Pure fractions were evaporated to dryness to afford2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperazin-1-yl)ethyl)piperidin-1-yl)isoindoline-1,3-dione(794 mg, 98.75%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=454.

Step 5: Preparation of5-[4-[2-(4-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperazin-1-yl)ethyl]piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a stirred mixture of4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(200.00 mg, 0.549 mmol, 1.00 equivalent) and2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperazin-1-yl)ethyl]piperidin-1-yl]isoindole-1,3-dione(373.39 mg, 0.823 mmol, 1.50 equivalent) in DMF (3.00 mL) was addedNaBH(OAc)₃ (68.98 mg, 1.098 mmol, 2.00 equivalent) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 2 h at40° C. The mixture solution was purified by Prep-HPLC with the followingconditions (Column: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/min; Gradient: 6 B to 27 B in 16 min; 254/220 nm; RT1: 15.34 min) toafford5-[4-[2-(4-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperazin-1-yl)ethyl]piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(165 mg, 28.16%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.09(s, 1H), 9.30 (s, 1H), 7.80 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.44 (s,1H), 7.34 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.88 (s, 2H), 5.07 (dd,J=12.9, 5.5 Hz, 1H), 4.35 (s, 2H), 4.08 (d, J=12.7 Hz, 2H), 3.90 (s,7H), 3.58 (s, 7H), 3.27-3.21 (m, 5H), 3.01-2.82 (m, 3H), 2.64-2.53 (m,2H), 2.22 (t, J=6.5 Hz, 1H), 2.02 (d, J=12.0 Hz, 1H), 1.77 (d, J=12.6Hz, 2H), 1.63 (s, 3H), 1.22 (d, J=11.6 Hz, 2H), 1.02 (d, J=8.0 Hz, 4H).LCMS (ESI) m/z: [M+H]+=802.15.

Example 50—Preparation of3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]335zetidine-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

Step 1: Preparation of tert-butyl3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (25)

To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate(2.50 g, 14.433 mmol, 1.00 equivalent) and TsCl (4.13 g, 21.650 mmol,1.50 equivalent) in DCM were added DMAP (264.49 mg, 2.165 mmol, 0.15equivalent) and TEA (4.38 g, 43.300 mmol, 3.00 equivalent) in portionsat 0° C. under air atmosphere. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with Petroleum ether/EtOAc (1:1) to affordtert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.4g, 93.11%) as a brown oil. LCMS (ESI) m/z: [M+H]⁺=328.

Step 2: Preparation of tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate

To a solution of tert-butyl3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.40 g, 13.439mmol, 1.00 equivalent) and KI (0.22 g, 1.344 mmol, 0.10 equivalent) inDMF was added KHCO₃ (4.04 g, 40.318 mmol, 3.00 equivalent) in portionsat 100° C. under air atmosphere. The resulting mixture was washed with3×150 mL of EtOAc. The resulting mixture was concentrated under reducedpressure. The residue was purified by reverse flash chromatography withthe following conditions: column, C18 silica gel; mobile phase, MeCN inwater, 0% to 100% gradient in 40 min; detector, UV 254 nm. This resultedin tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate(1.73 g, 29.98%) as an off-white solid. LCMS (ESI) m/z: [M+H]⁺=430.

Step 3: Preparation of tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]azetidine-1-carboxylate,and tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]azetidine-1-carboxylate

A solution of tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (1.73 g, 4.029 mmol, 1.00 equivalent) and Zn(2.64 g, 40.286 mmol, 10.00 equivalent) in AcOH was stirred for 2 h at60° C. under air atmosphere. The resulting mixture was washed with 3×100mL of ethyl acetate. The resulting mixture was concentrated underreduced pressure. The crude product was used in the next step directlywithout further purification to afford tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]azetidine-1-carboxylate and tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]azetidine-1-carboxylate(2.73 g, 78.53%) as an off-white solid. LCMS (ESI) m/z: [M+H]⁺=432.

Step 4: Preparation of3-[6-(336zetidine-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine-2, 6-dione

To a solution of tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]azetidine-1-carboxylateand tert-butyl3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]azetidine-1-carboxylate(2.73 g, 3.164 mmol, 1.00 equivalent) and TFA (1.50 mL, 20.195 mmol,6.38 equivalent) in DCM was added Et₃SiH (3.68 g, 31.638 mmol, 10.00equivalent) in portions at room temperature under air atmosphere. Theresulting mixture was concentrated under reduced pressure. The crudeproduct (mg) was purified by Prep-HPLC with the following conditions(Column: Xcelect CSH F-pheny OBD Column, 19*250 mm, 5 μm; Mobile PhaseA: Water (0.05% TFA), Mobile Phase B: can; Flow rate: 30 mL/min;Gradient: 5 B to 21 B in 10 min; 254/220 nm; RT1: 7.20/8.67 min) toafford3-[6-(azetidin-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (165mg, 8.27%) as an off-white solid. LCMS (ESI) m/z: [M+H]⁺=316.

Step 5: Preparation of3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

To a stirred solution of 3-[6-(azetidin-3-yloxy)-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (75.00 mg, 0.238 mmol, 1.00 equivalent) and4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(86.67 mg, 0.238 mmol, 1.00 equivalent) in DMF was added NaBH(OAc)₃(100.82 mg, 0.476 mmol, 2.00 equivalent) dropwise at room temperatureunder air atmosphere for 2 hours. The crude product (mg) was purified byPrep-HPLC with the following conditions (Column: XSelect CSH Prep C18OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 15 B to 23 B in 12 min;254/220 nm; RT1: 10.38 min) to afford3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(18.9 mg, 11.69%) as an off-white solid. ¹H NMR (400 MHz, Methanol-d4) δ9.39 (d, J=0.8 Hz, 1H), 7.80 (d, J=4.5 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H),7.42 (d, J=5.4 Hz, 1H), 7.32-7.24 (m, 1H), 7.22 (d, J=3.2 Hz, 1H), 6.89(s, 2H), 5.35-5.19 (m, 1H), 5.16 (dd, J=13.3, 5.2 Hz, 1H), 4.84-4.69 (m,2H), 4.65 (s, 2H), 4.48 (d, J=10.6 Hz, 2H), 4.42 (s, 2H), 3.98 (d,J=22.6 Hz, 6H), 3.69 (s, 3H), 2.93 (ddd, J=17.6, 13.5, 5.4 Hz, 1H), 2.80(ddd, J=17.6, 4.7, 2.4 Hz, 1H), 2.52 (qd, J=13.2, 4.7 Hz, 1H), 2.21(dddd, J=14.5, 10.7, 6.9, 3.9 Hz, 2H), 1.23-1.12 (m, 2H), 1.09 (d, J=4.4Hz, 2H). LCMS (ESI) m/z: [M+H]⁺=664.

Example 51. Preparation of5-((7-((1-(4-(6-cyclopropyl-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]isoindole-1,3-dione(100.00 mg, 0.202 mmol, 1.00 equivalent) and4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(73.68 mg, 0.202 mmol, 1 equivalent) in MeOH (3.00 mL) was added NaBH₃CN(25.41 mg, 0.404 mmol, 2 equivalent). The resulting mixture was stirredat 40° C. for 4 hours. Without any additional work-up, the mixture waspurified by prep-HPLC (Column: Kinetex EVO C18 Column, 21.2*150.5 μm;Mobile Phase A: Water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate:25 mL/min; Gradient: 25 B to 50 B in 12 min; 254/220 nm; RT1:11.92 min)to give5-([7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)methyl]-7-azaspiro[3.5]nonan-2-yl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(35 mg, 20.53%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.13 (s,1H), 9.29 (s, 1H), 8.19 (s, 2H), 7.87-7.74 (m, 2H), 7.44 (s, 1H),7.35-7.21 (m, 2H), 6.74 (s, 2H), 5.12 (dd, J=12.8, 5.4 Hz, 1H), 4.99 (t,J=6.9 Hz, 1H), 3.82 (s, 6H), 3.60 (s, 2H), 3.59-3.57 (m, 3H) 2.93-2.84(m, 4H), 2.63 (s, 1H), 2.62-2.60 (s, 1H), 2.55 (s, 3H), 2.23 (d, J=6.9Hz, 3H), 2.20-2.15 (s, 1H), 2.10 (dd, J=15.2, 4.6 Hz, 4H), 1.80 (dd,J=12.0, 6.3 Hz, 2H), 1.69-1.60 (m, 4H), 1.60-1.50 (m, 2H) 1.47 (s, 1H),1.07 (d, J=11.5 Hz, 2H), 1.03-0.96 (m, 4H). LCMS (ESI) m/z:[M+H]⁺=843.55.

Example 52—Preparation of3-[6-([7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)methyl]-7-azaspiro[3.5]nonan-2-yl]oxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

To a stirred solution of4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde)and3-(1-oxo-6-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione)in DMF (10 mL) was added NaBH(OAc)₃ in portions at room temperature. Theresulting mixture was stirred for 12 h at room temperature. The crudeproduct was purified by Prep-HPLC to afford3-[6-([7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)methyl]-7-azaspiro[3.5]nonan-2-yl]oxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(14.6 mg, 8.0%) as an off-white solid. ¹H NMR (300 MHz, Methanol-d4) δ9.40 (s, 1H), 7.76 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.42 (d, J=6.3 Hz,1H), 7.25-7.14 (m, 2H), 6.89 (s, 2H), 5.16 (dd, J=13.3, 5.1 Hz, 1H),4.92-4.83 (m, 1H), 4.58-4.35 (m, 4H), 3.99 (s, 6H), 3.69 (s, 3H),3.67-3.44 (m, 4H), 3.28-2.63 (m, 9H), 2.61-2.46 (m, 2H), 2.36-1.86 (m,11H), 1.68 (q, J=13.1 Hz, 2H), 1.23-1.08 (m, 4H). LCMS (ESI) m/z:[M+H]⁺=830.01.

Example 53—Preparation of5-[7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

Step 1: Preparation of tert-butyl2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (5.00 g, 18.101mmol, 1.00 equivalent) and tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (4.10 g, 0.018 mmol, 1equivalent) in DMSO (50 mL) was added DIEA (9.36 g, 72.422 mmol, 4.00equivalent), the resulting solution was stirred at 100° C. for 4 hoursunder nitrogen atmosphere. The resulting mixture was diluted with EtOAc(500 mL), the resulting mixture was washed with 3×300 mL of water and300 mL saturated brine. The organic layer was dried over Na₂SO₄,filtered and evaporated to afford tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(9 g, crude) as a yellow solid. The crude product was used in the nextstep directly without further purification. LCMS (ESI) m/z: [M+H]⁺=483

Step 2: Preparation of5-[2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a solution of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(9.00 g, 18.651 mmol, 1.00 equivalent) in DCM (90.00 mL) was added TFA(30.00 mL), the resulting solution was stirred at 25° C. for 1 hour. Theresulting mixture were evaporated to dryness to afford5-[2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(11.4 g, crude) as a yellow solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=383.

Step 3: Preparation of tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate

To a stirred solution of5-[2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(3.00 g, 7.845 mmol, 1.00 equivalent) and tert-butyl3-formylazetidine-1-carboxylate (1.45 g, 7.845 mmol, 1.00 equivalent) inDMF (30.00 mL) was added NaBH(OAc)₃ (3.33 g, 15.690 mmol, 2 equivalent),the resulting solution was stirred at 25° C. for 12 hours. The reactionmixture was diluted with EA (500 mL). The resulting mixture was washedwith 3×300 mL of water and 300 mL saturated brine. The organic layer wasdried over Na₂SO₄, filtered and evaporated to afford tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate(3.13 g, 72.33%) as a yellow solid that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]⁺=552

Step 4: Preparation of5-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a stirred solution of tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate(3.13 g, 5.674 mmol, 1.00 equivalent) in DCM (30.00 mL) was added TFA(10.00 mL), the resulting solution was stirred at 25° C. for 1 hour. Theresulting mixture were evaporated to dryness to afford5-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(4.1 g, crude) as a yellow solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=452

Step 5: Preparation of5-[7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a stirred solution of5-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(110.00 mg, 0.244 mmol, 1.00 equivalent) and4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(88.77 mg, 0.244 mmol, 1.00 equivalent) in MeOH (2.00 mL, 24.699 mmol,1115.22 equivalent) was added NaBH₃CN (30.62 mg, 0.487 mmol, 2.00equivalent). The resulting mixture was stirred for overnight at roomtemperature. The mixture solution was purified by Prep-HPLC with thefollowing conditions (Column: XSelect CSH Prep C18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flowrate: 25 mL/min; Gradient: 5 B to 27 B in 15 min; 254/220 nm; RT1:12.38min) to afford5-[7-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(63.9 mg, 31.71%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=800. ¹H NMR(400 MHz, Methanol-d4) δ 9.39 (s, 1H), 7.79 (d, J=6.3 Hz, 1H), 7.68 (d,J=8.4, 1.2 Hz, 1H), 7.41 (d, J=2.9 Hz, 1H), 6.88 (s, 3H), 6.76-6.67 (m,1H), 5.13-5.02 (m, 1H), 4.55 (d, 2H), 4.40 (t, J=9.3 Hz, 2H), 4.29-4.11(m, 2H), 4.05-3.76 (m, 10H), 3.69 (s, 3H), 3.61-3.43 (m, 5H), 3.22-2.98(m, 2H), 2.94-2.80 (m, 1H), 2.79-2.65 (m, 2H), 2.43-1.93 (m, 6H),1.27-1.14 (m, 2H), 1.14-1.05 (m, 2H).

Example 54—Preparation of5-[4-[2-(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

Step 1: tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (3.00 g, 10.861mmol, 1.00 equivalent) and tert-butyl piperazine-1-carboxylate (2.02 g,10.861 mmol, 1.00 equivalent) in NMP (30.00 mL) was added DIPEA (4.21 g,32.574 mmol, 3.00 equivalent). The resulting mixture was stirred for 2hours at 90° C. under nitrogen atmosphere. The resulting mixture wasdiluted with water (100 mL). The aqueous layer was extracted with EtOAc(3×30 mL). The resulting mixture was concentrated under reducedpressure. The residue was purified by reverse flash chromatography withthe following conditions: column, C18 silica gel; mobile phase, MeCN inwater, 5% to 90% gradient in 30 min; detector, UV 254 nm. This resultedin tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate(1.6 g, 33.29%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=443.

Step 2:2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione

To a stirred solution of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate(2.10 g, 4.746 mmol, 1.00 equivalent) in DCM (32.00 mL) was added TFA(8.00 mL). The resulting mixture was stirred for 2 hours at roomtemperature. The resulting mixture was concentrated under vacuum toafford 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione(2.6 g, 160%) as a yellow solid. That was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=343.

Step 3: tert-butyl4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (2.00g, 5.842 mmol, 1.00 equivalent) in DMF (25.00 mL) were added tert-butyl4-(2-oxoethyl)piperidine-1-carboxylate (1.33 g, 5.842 mmol, 1.00equivalent) under nitrogen atmosphere. The resulting mixture was stirredfor 16 hours at 15° C. under nitrogen atmosphere. To the above mixturewas added NaBH(OAc)₃ (2.48 g, 11.684 mmol, 2.00 equivalent) at 15° C.The resulting mixture was stirred for additional 2 hours at 15° C. Theresulting mixture was diluted with water (70 mL). The aqueous layer wasextracted with EtOAc (4×30 mL). The organic layers were concentratedunder vacuum. The residue was purified by silica gel columnchromatography, eluted with DCM:MeOH (50:1 to 10:1) to afford tert-butyl4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate(3 g, 92.75%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=555.

Step 4:2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione

To a stirred solution tert-butyl4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate(3.00 g, 5.418 mmol, 1.00 equivalent) in DCM (20.00 mL) was added TFA(5.00 mL) at room temperature. The resulting mixture was stirred forovernight at room temperature. The resulting mixture was concentratedunder vacuum to afford2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(3.5 g, 126.33%) as a yellow oil. That was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=454.

Step 5:5-[4-[2-(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

To a stirred solution of4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(150.00 mg, 0.412 mmol, 1.00 equivalent) and2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(186.69 mg, 0.412 mmol, 1.00 equivalent) in DMF (3.00 mL) was addedNaBH(OAc)₃ (261.73 mg, 1.235 mmol, 3.00 equivalent) dropwise at roomtemperature under air atmosphere. The resulting mixture was stirred forovernight at room temperature. The mixture solution was purified byPrep-HPLC with the following conditions (Column: Xselect CSH F-PhenylOBD column, 19*250, 5 μm; Mobile Phase A: Water (0.05% TFA), MobilePhase B: ACN; Row rate: 25 mL/min; Gradient: 12 B to 12 B in 2 min;254/220 nm: RT1: 11.13 min) to afford5-[4-[2-(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(62 mg, 18.78%) as a light yellow solid, LCMS (ESI) m/z: [M+H]+=802.30,¹H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.77(dd, J=8, 4, 4.8 Hz, 1H), 7.51-7.40 (m, 2H), 7.40-7.32 (m, 1H), 6.85 (s,2H), 5.13-5.03 (m, 1H), 4.24 (s, 4H), 3.88 (s, 6H), 3.57 (s, 5H), 3.44(d, J=11.9 Hz, 2H), 3.20 (q, J=10.4, 9.5 Hz, 6H), 3.02 (t, J=12.2 Hz,2H), 2.94-2.80 (m, 1H), 2.65-2.56 (m, 1H), 2.54 (d, J=4.9 Hz, 1H),2.30-2.19 (m, 1H), 2.08-1.99 (in, 1H), 1.91-1.70 (m, 3H), 1.67-1.41 (m,4H), 1.11-0.98 (m, 4H).

Example 55. Preparation of3-(6-[4[2-(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dioneformic acid

To a stirred solution of3-(1-oxo-6-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]-3H-isoindol-2-yl)piperidine-2,6-dione(160.00 mg, 0.364 mmol, 1.00 equivalent) and4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde(132.64 mg, 0.364 mmol, 1.00 equivalent) in DMF (2.00 mL) was addedNaBH(AcO)₃ (154.29 mg, 0.728 mmol, 2.00 equivalent) and titaniumisopropoxide (10.35 mg, 0.036 mmol, 0.10 equivalent). The resultingmixture was stirred for 28 h at room temperature. The mixture solutionwas purified by Prep-HPLC with the following conditions: Column: XselectCSH F-Phenyl OBD column, 19*250, 5 μm; Mobile Phase A: Water (0.05% FA),Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 8 B to 19 B in 10min; 220/254 nm; RT1: 8.28 min. This resulted in3-(6-[4-[2-(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione;formic acid (16.6 mg, 5.78%) as a white solid. LCMS (ESI) m/z:[M+H]+=788. ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.28 (s, 1H),8.18 (s, 4H, FA), 7.80 (s, 1H), 7.45-7.39 (m, 2H), 7.26 (dd, J=8.4, 2.4Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.74 (s, 2H), 5.10 (dd, J=13.3, 5.1 Hz,1H), 4.39-4.16 (m, 2H), 3.82 (s, 6H), 3.60 (s, 3H), 3.56 (s, 4H), 3.18(s, 5H), 2.90 (d, J=11.6 Hz, 3H), 2.73-2.56 (m, 3H), 2.35-2.32 (m, 2H),2.30-2.22 (m, 1H), 2.18-2.08 (m, 2H), 2.05-1.90 (m, 1H), 1.64 (d, J=12.3Hz, 2H), 1.39 (d, J=7.7 Hz, 2H), 1.26-1.19 (m, 1H), 1.19-1.09 (m, 2H),0.99 (dd, J=10.0, 3.7 Hz, 4H).

Example 56—Preparation of4-(6-cyclopropyl-2-(methyl-d3)-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde

Step 1: Preparation of 6-chloro-2-(2H3)methyl-2,7-naphthyridin-1-one

A solution of 6-chloro-2H-2,7-naphthyridin-1-one (500.00 mg, 2.769 mmol,1.00 equivalent) in THF (5.00 mL) was treated with NaH (132.89 mg, 5.537mmol, 2.00 equivalent) for 5 min at 0° C. followed by the addition ofCD₃I (802.69 mg, 5.537 mmol, 2.00 equivalent) in portions at 0° C. Afterstirring at 0° C. for 1 h, the reaction mixture was poured intoice-water (50 mL), the precipitated solids were collected by filtrationand washed with water (3×50 mL), then the solid was dried under vacuumto afford 6-chloro-2-(2H3)methyl-2,7-naphthyridin-1-one (500 mg, 91.37%)as a light yellow solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=198.

Step 2: Preparation of6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one

A mixture of 6-chloro-2-(2H3)methyl-2,7-naphthyridin-1-one (400.00 mg,2.024 mmol, 1.00 equivalent), cyclopropylboronic acid (260.78 mg, 3.036mmol, 1.50 equivalent), K₃PO₄ (1288.81 mg, 6.072 mmol, 3.00 equivalent),PCy₃ (113.51 mg, 0.405 mmol, 0.20 equivalent) and Pd(AcO)₂ (45.44 mg,0.202 mmol, 0.10 equivalent) in Toluene (20.00 mL) and H₂O (1.00 mL) wasstirred for 2 h at 110° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(10:1) to afford 6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (350mg, 85.08%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=204

Step 3: Preparation of4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one

A mixture of 6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (300.00mg, 1.476 mmol, 1.00 equivalent) and NBS (315.23 mg, 1.771 mmol, 1.20equivalent) in ACN (3.00 mL) was stirred for 2 h at 90° C. The resultingmixture was diluted with 1×50 mL of water. The resulting mixture wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith water (3×50 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The resulting mixturewas concentrated under reduced pressure. to afford4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (350 mg,84.04%) as a yellow solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=282.

Step 4: Preparation of4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

A mixture of 4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one(350.00 mg, 1.240 mmol, 1.00 equivalent),2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(434.86 mg, 1.489 mmol, 1.20 equivalent), Cs₂CO₃ (808.33 mg, 2.481 mmol,2.00 equivalent) and Pd(dppf)Cl₂ (90.76 mg, 0.124 mmol, 0.10 equivalent)in dioxane (3.00 mL) and H₂O (1.00 mL) was stirred for 3 hours at 90° C.under nitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford4-[6-cyclopropyl-2 (2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde (200 mg,43.88%) as an orange solid. LCMS (ESI) m/z: [M+H]⁺=368.

Example 57—Preparation of5-(7-[[1-([4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid

A mixture of4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(120.00 mg, 0.327 mmol, 1.00 equivalent),2-(2,6-dioxopiperidin-3-yl)-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]isoindole-1,3-dione(161.54 mg, 0.327 mmol, 1.00 equivalent) and NaBH(AcO)₃ (138.44 mg,0.653 mmol, 2.00 equivalent) in DMF (3.00 mL) was stirred for 2 hours atroom temperature. Without any additional work-up, the mixture waspurified by Prep-HPLC with the following conditions (Column: XSelect CSHPrep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.05% FA),Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10 B to 18 B in 15min; 254/220 nm; RT1:12.37; RT2:; Injection Volume: mL; Number Of Runs;)to afford5-(7-[[1-([4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid (12.2 mg) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 9.29 (s, 1H), 8.20 (s, 1H, FA), 7.78 (s, 1H), 7.64 (d,J=8.2 Hz, 1H), 7.40 (s, 1H), 6.76 (d, J=4.0 Hz, 3H), 6.64 (dd, J=8.4,2.1 Hz, 1H), 5.05 (dd, J=12.9, 5.4 Hz, 1H), 3.84 (s, 6H), 3.79 (s, 2H),3.74 (s, 4H), 3.55 (s, 3H), 3.13 (s, 3H), 2.97-2.79 (m, 1H), 2.71-2.56(m, 2H), 2.46 (d, J=7.0 Hz, 2H), 2.36-2.21 (m, 4H), 2.05-1.95 (m, 1H),1.78-1.69 (m, 4H), 1.00 (dd, J=6.6, 4.3 Hz, 4H). LCMS (ESI) m/z:[M+H]⁺=803.

Example 58—Preparation of5-[(7-[[1-([4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

A mixture of4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(60.00 mg, 0.163 mmol, 1.00 equivalent),2-(2,6-dioxopiperidin-3-yl)-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]isoindole-1,3-dione(80.77 mg, 0.163 mmol, 1.00 equivalent) and NaBH(AcO)₃ (69.22 mg, 0.327mmol, 2.00 equivalent) in DCM (2.00 mL) was stirred for 2 hours at roomtemperature. The crude product was purified by Prep-HPLC with thefollowing conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250mm, 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flowrate: 25 mL/min; Gradient: 16 B to 21 B in 13 min; 254/220 nm; RT1:10.97min) to afford5-[(7-[[1-([4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(11.1 mg) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.38 (s,1H), 8.56 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.66 (s, 1H), 7.38 (d, J=0.9Hz, 1H), 7.31-7.20 (m, 2H), 6.86 (s, 2H), 5.13 (dd, J=12.4, 5.4 Hz, 1H),4.32 (s, 2H), 3.97 (s, 6H), 3.50 (d, J=12.2 Hz, 2H), 3.03 (s, 2H),2.91-2.70 (m, 3H), 2.51 (d, J=8.6 Hz, 6H), 2.33 (d, J=6.7 Hz, 2H),2.21-2.08 (m, 2H), 2.07-1.89 (m, 5H), 1.83-1.70 (m, 4H), 1.51 (s, 2H),1.17-1.04 (m, 4H). LCMS (ESI) m/z: [M+H]+=846.

Example 59—Preparation of5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid

Step 1: Preparation of 2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one

To a solution of 6-chloro-2-methyl-2,7-naphthyridin-1-one (300.0 mg,1.541 mmol, 1.00 equivalent) and 3-bromooxetane (422.3 mg, 3.083 mmol,2.00 equivalent) in DMF (3.00 mL) was added Zn (302.5 mg, 4.624 mmol,3.00 equivalent) and NaI (57.8 mg, 0.385 mmol, 0.25 equivalent). Theresulting mixture was stirring at 60° C. for 12 hours under a nitrogenatmosphere. The resulting mixture was concentrated. The crude mixturewas purified by reverse phase column directly with the followingconditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 45 mL/min; Gradient: 8% B to 80% B in 20 min; 254/220 nm) toafford 2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one (150 mg, 45.0%)as a white solid. LCMS (ESI) m/z: [M+H]⁺=217.

Step 2: Preparation of 4-bromo-2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one

To a solution of 2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one (100.0mg, 0.462 mmol, 1.00 equivalent) in DMF (3.00 mL) was added NBS (90.5mg, 0.509 mmol, 1.10 equivalent). The resulting mixture was stirring at25° C. for 2 hours. The resulting mixture was concentrated. The crudemixture was purified by reverse phase column directly with the followingconditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 45 mL/min; Gradient: 8% B to 80% B in 20 min; 254/220 nm) toafford 4-bromo-2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one (105 mg,76.9%) as a white solid. LCMS (ESI) m/z: [M+H]+=295.

Step 3: Preparation of2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]benzaldehyde

To a solution of 4-bromo-2-methyl-6-(oxetan-3-yl)-2,7-naphthyridin-1-one(100.0 mg, 0.339 mmol, 1.00 equivalent) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(148.5 mg, 0.508 mmol, 1.50 equivalent) in dioxane (3.00 mL) and H₂O(1.00 mL) were added Cs₂CO₃ (331.2 mg, 1.016 mmol, 3.00 equivalent) andPd(dppf)Cl₂ (24.8 mg, 0.034 mmol, 0.10 equivalent) under nitrogenatmosphere. The resulting mixture was stirring at 80 degree for 3 hoursunder nitrogen atmosphere. The resulting mixture was concentrated. Thecrude mixture was purified by reverse phase column directly with thefollowing conditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B:ACN; Flow rate: 45 mL/min; Gradient: 8% B to 80% B in 20 min; 254/220nm) to afford. This resulted in (130 mg, crude) of2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]benzaldehyde(110 mg, 85.3%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=381.

Step 4: Preparation of5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid

To a stirred mixture of2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]benzaldehyde(50.0 mg, 0.131 mmol, 1.00 equivalent) and2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperazin-1-yl)ethyl]piperidin-1-yl]isoindole-1,3-dione(65.6 mg, 0.145 mmol, 1.10 equivalent) in DMF (2.00 mL) was addedNaBH(OAc)₃ (55.72 mg, 0.263 mmol, 2.00 equivalent) at room temperature.The above mixture was stirred for 3 hours. Then the crude reactionmixture was directly purified by Prep-HPLC (Column: Xselect CSH F-phenylOBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 15% B to 24% B in 14 min;254/220 nm; Rt: 12.97 min). This resulted in5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-6-(oxetan-3-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid (40 mg, 37.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.08 (s, 1H), 9.50 (s, 1H), 8.15 (s, 1H, FA), 7.87 (s, 1H), 7.65 (d,J=8.5 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.8,2.3 Hz, 1H), 6.74 (s, 2H), 5.07 (dd, J=13.0, 5.3 Hz, 1H), 4.89 (dd,J=8.4, 5.5 Hz, 2H), 4.79 (dd, J=6.7, 5.5 Hz, 2H), 4.59-4.47 (m, 1H),4.04 (d, J=13.0 Hz, 2H), 3.81 (s, 6H), 3.58 (d, J=8.8 Hz, 6H), 3.00-2.82(m, 3H), 2.73-2.57 (m, 4H), 2.55-2.41 (m, 4H), 2.40-2.23 (m, 3H),2.05-1.97 (m, 1H), 1.78-1.71 (m, 2H), 1.66-1.51 (m, 1H), 1.42-1.34 (m,2H), 1.24-1.11 (m, 2H). LCMS (ESI) m/z: [M+H]+=818.60.

Example 60—Preparation of3-[5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

Step 1: Preparation of4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile

To a stirred solution of 5-bromo-4-methyl-2-(trifluoromethyl)pyridine(500.00 mg, 2.083 mmol, 1.00 equivalent) and Zn(CN)₂ (146.79 mg, 1.250mmol, 0.6 equivalent) in DMF (5.00 mL) was added Pd₂(dba)₃ (38.15 mg,0.042 mmol, 0.02 equivalent) and DPPF (46.03 mg, 0.083 mmol, 0.04equivalent), the resulting solution was stirred at 120° C. for 3 hours.Without any additional work-up, the mixture was purified by flashC18-flash chromatography, elution gradient 0 to 80% MeCN in water(containing 0.1% NH₄HCO₃). Pure fractions were evaporated to dryness toafford 4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile (220 mg,56.74%) as a yellow oil. LCMS (ESI) m/z: [M+H]⁺=187.

Step 2: Preparation of4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide

To a stirred solution of4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile (200.00 mg, 1.074mmol, 1.00 equivalent) and NH₃.H₂O (1.00 mL) in EtOH (1.00 mL) was addedH₂O₂ (0.20 mL), the resulting solution was stirred at 25° C. for 4hours. The reaction mixture was concentrated under reduced pressure toafford 4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide (372 mg,crude) as a white solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=205.

Step 3: Preparation ofN-[(1Z)-(dimethylamino)methylidene]-4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide

To a stirred solution of4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide (350.00 mg, 1.714mmol, 1.00 equivalent) and DMF-DMA (306.44 mg) in2-methyltetrahydrofuran (5.00 mL) was stirred at 80° C. for 2 hours.Then the mixture was concentrated under reduced pressure to affordN-[(1Z)-(dimethylamino)methylidene]-4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide(360 mg crude) as a yellow solid that was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=260.

Step 4: Preparation of 6-(trifluoromethyl)-2H-2,7-naphthyridin-1-one

To a stirred solution ofN-[(1Z)-(dimethylamino)methylidene]-4-methyl-6-(trifluoromethyl)pyridine-3-carboxamide(350.00 mg, 1.350 mmol, 1.00 equivalent) and t-BuOK (227.25 mg, 2.025mmol, 1.50 equivalent) in THF (4.00 mL) was stirred at 60° C. for 2hours. The resulting mixture was cooled and concentrated under reducedpressure, the residue was washed with saturated NaHCO₃ solution (100mL). Then the solid was dried under vacuum to give6-(trifluoromethyl)-2H-2,7-naphthyridin-1-one (295 mg, crude) as anoff-white solid. The crude product was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=215.

Step 5: Preparation of 2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one

To a stirred mixture of 6-(trifluoromethyl)-2H-2,7-naphthyridin-1-one(275.00 mg, 1.284 mmol, 1.00 equivalent) in anhydrous DMF (3.00 mL) wasadded NaH (36.98 mg, 1.541 mmol, 1.20 equivalent, 60%) in portions at 0°C. After 10 minutes, to above mixture was added Mel (546.82 mg, 3.852mmol, 3.00 equivalent) at 0° C. and the mixture was allowed to stir for10 min at 0° C. Then the mixture was allowed to stir for 12 hr at roomtemperature under nitrogen atmosphere. The crude solid was slurried withwater (100 mL), and the solid was filtered and collected to give the2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one (242 mg, 82.59%) asa yellow solid, that was used directly without further purification.LCMS (ESI) m/z: [M+H]⁺=229.

Step 6: Preparation of 4-bromo-2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one

To a stirred mixture of2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one (220.00 mg, 0.964mmol, 1.00 equivalent) in anhydrous DMF (5.00 mL) was added NBS (188.77mg, 1.061 mmol, 1.10 equivalent), the mixture was stirred at 90° C. for2 hours. Without any additional work-up, the residue was purified byPrep-TLC (PE/EtOAc 1:1) to afford4-bromo-2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one (192 mg,64.85%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=307.

Step 7: Preparation of2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]benzaldehyde

To a solution of4-bromo-2-methyl-6-(trifluoromethyl)-2,7-naphthyridin-1-one (142.00 mg,0.462 mmol, 1.00 equivalent) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(189.13 mg, 0.647 mmol, 1.4 equivalent) in dioxane (3.00 mL) was addedPd(dppf)Cl₂ (33.84 mg, 0.046 mmol, 0.10 equivalent) and Cs₂CO₃ (301.34mg, 0.925 mmol, 2 equivalent), the resulting solution was stirred at 70°C. for 3 hours. Without any additional work-up, the residue was purifiedby silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) toafford2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]benzaldehyde(275 mg, crude) as a brown solid, that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=393.

Step 8: Preparation of3-[5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

To a solution of2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]benzaldehyde(78.00 mg, 0.199 mmol, 1.00 equivalent) and3-(1-oxo-5-[4-[2-(piperazin-1-yl)ethyl]piperidin-1-yl]-3H-isoindol-2-yl)piperidine-2,6-dione(131.08 mg, 0.298 mmol, 1.50 equivalent) in DMF (2.00 mL) was addedNaBH(OAc)₃ (84.27 mg, 0.398 mmol, 2 equivalent), the resulting solutionwas stirred at 25° C. for 12 hours. Without any additional work-up, themixture was purified by prep-HPLC (Column: SunFire Prep C18 OBD Column,19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B:ACN; Flow rate: 25 mL/min; Gradient: 10 B to 32 B in 10 min; 254/220 nm;RT1: 8.95 min) to afford3-[5-(4-[2-[4-([2,6-dimethoxy-4-[2-methyl-1-oxo-6-(trifluoromethyl)-2,7-naphthyridin-4-yl]phenyl]methyl)piperazin-1-yl]ethyl]piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(25 mg, 15.41%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6) δ10.96 (s, 1H), 9.59 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.52 (d, J=8.5Hz, 1H), 7.06 (d, J=8.2 Hz, 2H), 6.94 (d, J=18.1 Hz, 2H), 5.05 (dd,J=13.4, 5.1 Hz, 1H), 4.38-4.15 (m, 3H), 3.87 (s, 8H), 3.67 (s, 3H), 3.63(s, 3H), 3.11-3.25 (m, 4H), 2.87 (dt, J=36.3, 12.4 Hz, 6H), 2.59 (d,J=18.0 Hz, 2H), 2.36-2.29 (m, 1H), 2.00-1.91 (m, 1H), 1.75 (d, J=12.5Hz, 2H), 1.57 (s, 3H), 1.25 (d, J=11.0 Hz, 2H). LCMS (ESI) m/z:[M+H]⁺=816.15.

Example 61—Preparation of3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

Step 1: Preparation of 6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one

To a solution of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (5.00g, 18.281 mmol, 1.00 equivalent) and azetidine hydrochloride (3.2 g,54.843 mmol, 3 equivalent) in DMSO (50.00 mL) was added K₂CO₃ (12.6 g,91.404 mmol, 5 equivalent). The resulting solution was stirred at 130°C. for 2 hours. The resulting mixture was cooled and diluted with water(100 mL), and then extracted with EtOAc (3×100 mL). The combined organiclayers were washed with saturated NaCl solution (3×50 mL), dried overanhydrous Na₂SO₄, concentrated under reduced pressure to afford6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one (3.7 g, 68.8%)as a grey solid, that was used directly without further purification.LCMS (ESI) m/z: [M+H]⁺=294.

Step 2: Preparation of4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

To a solution of6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one (1.42 g, 4.827mmol, 1.00 equivalent) and 4-formyl-3,5-dimethoxyphenylboronic acid(1.52 g, 7.241 mmol, 1.5 equivalent) in dioxane (16.00 mL) and H₂O (4.00mL) were added Pd(dppf)Cl₂ (353.2 mg, 0.483 mmol, 0.1 equivalent) andCs₂CO₃ (3.15 g, 9.655 mmol, 2 equivalent), and the resulting solutionwas stirred at 70° C. for 2 hours. The resulting mixture was cooled andconcentrated under reduced pressure. The residue was slurried with water(30 mL) and filtered, the filter cake was collected. And this solid wasfurther slurried with MeOH (30 mL) and filtered. The solid was collectedto afford product to afford4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(1.42 g, 77.5%) as a grey and solid. LCMS (ESI) m/z: [M+H]⁺=380.

Example 62—Preparation of3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

Step 1: Preparation of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a stirred solution of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(500.0 mg, 1.036 mmol, 1.00 equivalent) in AcOH (4.00 mL) was added Zn(677.7 mg, 10.362 mmol, 10.00 equivalent). The resulting mixture wasstirred at 60° C. for 2 h. The reaction mixture was filtered, and thefiltrate was evaporated to afford crude product. The crude product waspurified by reverse phase column, elution gradient 0 to 30% MeCN inwater (containing 0.1% formic acid). Pure fractions were evaporated todryness to afford tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (277.3 mg, 55.2%) as a yellow solid. LCMS(ESI) m/z: [M+H]⁺=485.

Step 2: Preparation of3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

To a stirred solution of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(250.0 mg, 0.516 mmol, 1.00 equivalent) in DCM (2.00 mL) were added TFA(0.50 mL) and Et₃SiH (0.20 mL). The resulting mixture was stirred atroom temperature for 1 hour. The resulting mixture was concentratedunder reduced pressure. This resulted in3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(267.5 mg, crude) as a yellow gum. The crude product was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]⁺=369.

Step 3: Preparation of3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid

To a stirred solution of3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(400.0 mg, 1.086 mmol, 1.00 equivalent) and4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(494.3 mg, 1.303 mmol, 1.20 equivalent) in DMF (3.00 mL) was addedNaBH(OAc)₃ (920.4 mg, 4.343 mmol, 4.00 equivalent) at room temperature.The resulting mixture was stirred at room temperature for 2 hours. Thecrude reaction solution was directly purified by Prep-HPLC with thefollowing conditions (Column: XSelect CSH Prep C18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flowrate: 25 mL/min; Gradient: 14 B to 22 B in 15 min; 254/220 nm; RT1:11.72 min) to afford3-[6-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid (99.2 mg, 12.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 10.94 (s, 1H), 9.02 (s, 1H), 8.15 (s, 1H, FA), 7.61 (s, 1H), 7.48 (d,J=8.2 Hz, 1H), 6.75 (s, 2H), 6.53-6.44 (m, 2H), 6.21 (s, 1H), 5.04 (dd,J=13.3, 5.2 Hz, 1H), 4.30 (d, J=17.0 Hz, 1H), 4.17 (d, J=16.9 Hz, 1H),4.01 (t, J=7.4 Hz, 4H), 3.83 (s, 6H), 3.61 (d, J=13.2 Hz, 6H), 3.48 (s,3H), 2.96-2.84 (m, 1H), 2.63-2.54 (m, 3H), 2.51-2.45 (m, 2H), 2.35 (q,J=6.6 Hz, 3H), 1.95 (d, J=12.9 Hz, 1H), 1.75 (s, 4H). LCMS (ESI) m/z:[M+H]⁺=732.45.

Example 63—Preparation of3-[5-(7-[[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dionebis(formic acid)

Step 1: Preparation of methyl 5-bromo-2-(bromomethyl)benzoate

A solution of methyl 5-bromo-2-methylbenzoate (1.0 g, 4.365 mmol, 1.00equivalent), BPO (223.7 mg, 0.873 mmol, 0.20 equivalent) and NBS (777.0mg, 4.365 mmol, 1.00 equivalent) in solvent CCl₄ (10.00 mL) was stirredat 80 degree for 3 hours. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column, eluted with petroleumether/EtOAc (20:1) to afford methyl 5-bromo-2-(bromomethyl)benzoate (1.1g, 81.8%) as a light-yellow liquid.

Step 2: Preparation of3-(6-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (1.0 g, 3.247mmol, 1.00 equivalent), 3-aminopiperidine-2,6-dione (499.26 mg, 3.896mmol, 1.20 equivalent) in solvent DMF (10.00 mL) was added DIEA (1.26 g,9.741 mmol, 3.00 equivalent) at room temperature, and the resultingsolution was stirred at 80 degree for 12 hours. The resulting mixturewas concentrated. The residue was dissolved in water (100 mL) andextracted with 30% i-PrOH/CH₂Cl₂ (100 mL×3). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to afford of3-(6-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (500 mg, 47.7%)as a grey solid. LCMS (ESI) m/z: [M+H]⁺=323.

Step 3: Preparation of4-[6-[7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]-4-carbamoylbutanoicacid

To a mixture of 3-(6-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(500.0 mg, 1.547 mmol, 1.00 equivalent), tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (350.2 mg, 1.547 mmol, 1.00equivalent), Cs₂CO₃ (1.51 g, 4.642 mmol, 3.00 equivalent) and RuPhosPalladacycle Gen 3 (129.4 mg, 0.155 mmol, 0.10 equivalent) was addedsolvent dioxane (5.00 mL) under nitrogen atmosphere, and the resultingmixture was stirred at 100 degree for 6 hours under nitrogen atmosphere.The resulting mixture was concentrated. The crude product was purifiedby reverse phase column directly with the following conditions (MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 45 mL/min;Gradient: 8% B to 80% B in 20 min; 254/220 nm) to afford4-[6-[7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]-4-carbamoylbutanoicacid (150 mg, 19.9%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=487.

Step 4: Preparation of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a solution of4-[6-[7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]-4-carbamoylbutanoicacid (200.0 mg, 0.411 mmol, 1.00 equivalent) in solvent CH₃CN (5.00 mL)was added CDI (133.3 mg, 0.822 mmol, 2.00 equivalent). The resultingsolution was stirred at 80 degree for 6 hours. The resulting mixture wasconcentrated. The crude product was purified by reverse phase columndirectly with the following conditions (Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 45 mL/min; Gradient: 8% B to 80% B in 20min; 254/220 nm) to afford tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(170 mg, 88.3%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=469.

Step 5: Preparation of3-(6-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

To a solution of tert-butyl2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(100.0 mg, 0.213 mmol, 1.00 equivalent) in DCM (3.00 mL) was added TFA(1.00 mL) at room temperature. The resulting mixture was stirred for 1hour at room temperature. It was then concentrated in vacuo to give acrude product which was used directly in the next step. LCMS (ESI) m/z:[M+H]⁺=369.

Step 6: Preparation of tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate

To a solution of3-(6-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(100.0 mg, 0.271 mmol, 1.00 equivalent), tert-butyl3-formylazetidine-1-carboxylate (50.3 mg, 0.271 mmol, 1.00 equivalent)in solvent DMF (3.00 mL) was added NaBH(OAc)₃ (172.6 mg, 0.814 mmol,3.00 equivalent). The resulting solution was stirred at 25 degree for 3hours. The mixture was concentrated. The crude product was purified byreverse phase column directly with the following conditions (MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 45 mL/min;Gradient: 8% B to 80% B in 20 min; 254/220 nm) to afford tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate(60 mg, 41.1%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=538.

Step 7: Preparation of3-[6-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

To a solution of tert-butyl3-([2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl)azetidine-1-carboxylate(100.0 mg, 0.186 mmol, 1.00 equivalent) in DCM (3.00 mL) was added TFA(1.00 mL) at room temperature. The resulting mixture was stirred for 1hour at room temperature. It was then concentrated in vacuo to give acrude product which was used directly in the next step. LCMS (ESI) m/z:[M+H]⁺=438.

Step 8:3-[5-(7-[[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione bis(formic acid)

To a stirred solution of3-[5-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(35.0 mg, 0.080 mmol, 1.00 equivalent) and4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(30.4 mg, 0.080 mmol, 1.00 equivalent) in DMF (4.00 mL) was addedNaBH(OAc)₃ (50.9 mg, 0.240 mmol, 3.00 equivalent) at room temperature.The resulting mixture was stirred for overnight at room temperature. Themixture was filtered, and the filtrate was purified by Prep-HPLC(Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile PhaseA: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min;Gradient: 5 B to 17 B in 12 min; 254/220 nm; RT1: 8.9-9.53 min) toafford3-[6-(7-[[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)azetidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;bis(formic acid) (5.1 mg, 7.6%) as a light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 10.97 (s, 1H), 9.02 (s, 1H), 8.18 (s, 2H, FA), 7.61 (s,1H), 7.38 (d, J=8.2 Hz, 1H), 6.79 (s, 2H), 6.68 (d, J=7.5 Hz, 2H), 6.18(s, 1H), 5.08 (dd, J=13.2, 5.1 Hz, 1H), 4.31 (d, J=16.6 Hz, 1H), 4.18(d, J=16.7 Hz, 1H), 4.11-3.97 (m, 6H), 3.86 (s, 6H), 3.82-3.69 (m, 4H),3.58 (s, 3H), 3.49 (s, 3H), 2.96-2.85 (m, 2H), 2.78-2.71 (m, 1H),2.64-2.60 (m, 1H), 2.59-2.55 (m, 1H), 2.43-2.26 (m, 7H), 2.06-1.95 (m,2H), 1.78-1.67 (m, 4H). LCMS (ESI) m/z: [M+H]⁺=800.96.

Example 64—Preparation of3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid; and3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione

To a stirred solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate(1.00 g, 2.265 mmol, 1.00 equivalent) in DCM (8 mL) was added TFA (2.00mL) at room temperature. The resulting mixture was stirred for 2 h atroom temperature. The resulting mixture was concentrated under reducedpressure. This resulted in2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione (1.23g, crude) as a white solid that was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=342.

Step 2: Preparation of3-[3-hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[1-hydroxy-3-oxo-5-(piperidin-4-yl)-1H-isoindol-2-yl]piperidine-2,6-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione (300.0mg, 0.879 mmol, 1.00 equivalent) in AcOH (5.00 mL) was added Zn (574.9mg, 8.788 mmol, 10 equivalent), and the resulting solution was stirredat 25° C. for 2 hours. The mixture was diluted with EtOAc (30 mL) andwashed with water (30 mL×3). The organic layers were combined and driedover anhydrous sodium sulfate, filtered and concentrated to give a crudeproduct. The crude product was purified by flash C18 chromatography(elution gradient 0 to 11% ACN in H₂O) to give3-[3-hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[1-hydroxy-3-oxo-5-(piperidin-4-yl)-1H-isoindol-2-yl]piperidine-2,6-dione(280 mg, mixture of two regio-isomers, 92.8%) as a white solid. LCMS(ESI) m/z: [M+H]⁺=344.

Step 3: Preparation of3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione

To a solution of3-[3-hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[1-hydroxy-3-oxo-5-(piperidin-4-yl)-1H-isoindol-2-yl]piperidine-2,6-dione(mixture of two regio-isomers, 260.0 mg, 0.757 mmol, 1.00 equivalent),4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(287.3 mg, 0.757 mmol, 1 equivalent) in DMF (3 mL) was added NaBH(OAc)₃(321.0 mg, 1.514 mmol, 2 equivalent), and the resulting solution wasstirred at 25° C. for 4 hours. The mixture was diluted with EtOAc (20mL) and washed with water (20 mL×3). The organic layers were combinedand dried over anhydrous sodium sulfate, filtered and concentrated togive a crude product. The crude product was purified by Prep-TLC(CH₂Cl₂/MeOH 10:1) to give3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione(208 mg, mixture of two regio-isomers, 38.9%) as a white solid. LCMS(ESI) m/z: [M+H]⁺=707.

Step 4: Preparation of3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione formic acid;and3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

To a solution of3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneand3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione(mixture of two regio-isomers, 200.0 mg, 0.141 mmol, 1.00 equivalent) inDCM (3.00 mL) was added TFA (2.00 mL, 26.926 mmol, 95.16 equivalent) andtriethylsilane (1.00 mL, 6.192 mmol, 21.88 equivalent), and theresulting solution was stirred at 25° C. for 1 hour. The crude productwas purified by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 5μm, 19*150 mm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN;Flow rate: 25 mL/min; Gradient: 3 B to 26 B in 14 minutes; 254 nm; RT1:13.32 min) to afford3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (39.5 mg,39.1%) and3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid (24.8 mg, 22.7%) both as a white solid.

For3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione: ¹H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.02 (s, 1H), 8.16 (s, 1H, FA), 7.68-7.60(m, 2H), 7.49 (s, 1H), 7.39 (dd, J=7.8, 1.4 Hz, 1H), 6.76 (s, 2H), 6.22(s, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.42 (d, J=17.3 Hz, 1H), 4.28(d, J=17.3 Hz, 1H), 4.01 (t, J=7.4 Hz, 4H), 3.84 (s, 6H), 3.69 (s, 2H),3.49 (s, 3H), 3.05 (d, J=11.2 Hz, 2H), 2.92 (ddd, J=17.3, 13.6, 5.4 Hz,1H), 2.66-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.46-2.38 (m, 1H), 2.37-2.28(m, 4H), 2.04-1.95 (m, 1H), 1.78-1.65 (m, 4H). LCMS (ESI) m/z:[M+H]⁺=691.35.

For3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione;formic acid: ¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.02 (s, 1H),8.18 (s, FA), 7.62 (s, 1H), 7.58-7.48 (m, 3H), 6.75 (s, 2H), 6.22 (s,1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.41 (d, J=17.1 Hz, 1H), 4.27 (d,J=17.1 Hz, 1H), 4.01 (t, J=7.4 Hz, 4H), 3.84 (s, 6H), 3.63 (s, 2H), 3.48(s, 3H), 3.00 (d, J=11.0 Hz, 2H), 2.97-2.85 (m, 1H), 2.65-2.60 (m, 1H),2.60-2.56 (m, 1H), 2.45-2.37 (m, 1H), 2.37-2.30 (m, 1H), 2.24 (t, J=11.3Hz, 2H), 2.03-1.96 (m, 1H), 1.80-1.73 (m, 2H), 1.73-1.62 (m, 2H). LCMS(ESI) m/z: [M+H]⁺=691.55.

Example 65—Preparation of3-(5-[[1-([2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

Step 1: Preparation of4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one

To a stirred solution of4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (547.00 mg, 2.000 mmol,1.00 equivalent) and morpholine (522.71 mg, 6.000 mmol, 3.00 equivalent)in DMSO (6.00 mL) was added K₂CO₃ (1382.00 mg, 10.000 mmol, 5.00equivalent). The resulting mixture was stirred for 1 h at 130° C. undernitrogen atmosphere. The reaction mixture was diluted with EA (100 mL).

The resulting mixture was washed with 3×100 mL of water and 1×100 mLsaturated brine. The organic layer was dried over Na₂SO₄, filtered andevaporated to afford crude product. The residue was purified by silicagel column chromatography, elution gradient 0 to 10% MeOH in DCM. Purefractions were evaporated to dryness to afford4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one (541 mg,83.44%) as a light yellow solid. LCMS (ESI) m/z: [M+H]⁺=324.

Step 2: Preparation of 2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4-yl]benzaldehyde

To a solution of4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one (540.00 mg,1.666 mmol, 1.00 equivalent) and 4-formyl-3,5-dimethoxyphenylboronicacid (454.73 mg, 2.165 mmol, 1.30 equivalent), Cs₂CO₃ (1628.20 mg, 4.997mmol, 3.00 equivalent) in H₂O (1.00 mL) and dioxane (5.00 mL) was addedPd(dppf)Cl₂ CH₂Cl₂ (136.03 mg, 0.167 mmol, 0.10 equivalent) undernitrogen. After stirring for 1 h at 90° C. under a nitrogen atmosphere,the resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, elutiongradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to drynessto afford 2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7naphthyridin-4-yl] benzaldehyde (356 mg, 52.20%) as a yellow solid. LCMS(ESI) m/z: [M+H]⁺=410.

Step 3: Preparation of 3-(5-[[1-([2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

To a stirred solution of3-[5-(azetidin-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(100.00 mg, 0.317 mmol, 1.00 equivalent) and2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4-yl]benzaldehyde(129.85 mg, 0.317 mmol, 1.00 equivalent) in DMF was added NaBH(OAc)₃(134.43 mg, 0.634 mmol, 2.00 equivalent) dropwise at room temperatureunder air atmosphere for 2 hours. The residue was purified by reverseflash chromatography with the following conditions: column, C18 silicagel; mobile phase, MeCN in water, 0% to 100% gradient in 45 min;detector, UV 254 nm. The crude product was purified by Prep-HPLC withthe following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250mm, 5 μm; Mobile Phase A: Water (0.05% FA); Mobile Phase B: ACN; Flowrate: 30 mL/min; Gradient: 13 B to 33 B in 14 min; 254/220 nm; RT1:12.85 min) to afford3-(5-[[1-([2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(100 mg, 44.15%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.18(s, 1H), 7.80 (t, J=6.7 Hz, 1H), 7.49 (s, 1H), 7.09 (t, J=7.3 Hz, 2H),6.88 (s, 2H), 6.63 (d, J=4.9 Hz, 1H), 5.40-5.20 (m, 1H), 5.15 (dd,J=13.3, 5.2 Hz, 1H), 4.77 (ddd, J=24.3, 12.5, 6.8 Hz, 2H), 4.65 (d,J=22.0 Hz, 2H), 4.48 (d, J=6.3 Hz, 2H), 4.44-4.28 (m, 2H), 3.96 (d,J=23.6 Hz, 6H), 3.78 (t, J=4.8 Hz, 4H), 3.61 (s, 3H), 3.56 (d, J=4.7 Hz,4H), 2.93 (ddd, J=18.5, 13.5, 5.3 Hz, 1H), 2.80 (ddd, J=17.5, 4.6, 2.3Hz, 1H), 2.49 (qd, J=13.2, 4.7 Hz, 1H), 2.23-2.14 (m, 1H). LCMS (ESI)m/z: [M+H]⁺=709.

Example 66—Preparation of3-[5-[(7-[[1-([4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

Step 1: Preparation of ethyl2-methyl-2-(7-methyl-8-oxo-2,7-naphthyridin-3-yl)propanoate

To a stirred mixture of LDA (825.63 mg, 7.707 mmol, 1.5 equivalent) inTHF (20 mL) was added ethyl isobutyrate (895.28 mg, 7.707 mmol, 1.5equivalent) dropwise at −78° C. under nitrogen atmosphere. The resultingmixture was stirred for 30 min at −78° C. under nitrogen atmosphere. Tothe above mixture was added 6-chloro-2-methyl-2,7-naphthyridin-1-one(1.00 g, 5.138 mmol, 1.00 equivalent) in THF (1 mL) dropwise over 2 minat −78° C. The resulting mixture was stirred for additional 2 hours atroom temperature. The reaction was quenched with aqueous NH₄Cl (5 mL) at0° C. The resulting mixture was extracted with CH₂Cl₂ (100 mL). Thecombined organic layers were washed with water (100 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The reaction mixture was purified by reverse phaseflash with the following conditions (Mobile Phase A: Water (0.3% FA);Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 5% B to 50% B in 30min) to afford ethyl2-methyl-2-(7-methyl-8-oxo-2,7-naphthyridin-3-yl)propanoate (320 mg,11.35%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=275.

Step 2: Preparation of6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one

To a stirred mixture of ethyl2-methyl-2-(7-methyl-8-oxo-2,7-naphthyridin-3-yl)propanoate (240.00 mg,0.875 mmol, 1.00 equivalent) in EtOH (20.00 mL) was added LiBH₄ (209.64mg, 9.624 mmol, 11.00 equivalent) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 16 h at roomtemperature under nitrogen atmosphere. The reaction was quenched withWater at room temperature. The resulting mixture was extracted withCH₂Cl₂ (20 mL). The combined organic layers were washed with water (2×20mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one (120mg, 53.14%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=233.

Step 3: Preparation of4-bromo-6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one

To a stirred mixture of6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one (90.00mg, 0.387 mmol, 1.00 equivalent) in DMF (1.00 mL) was added NBS (82.75mg, 0.465 mmol, 1.2 equivalent) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 2 hours at 80° C.under nitrogen atmosphere. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (17:1) to afford4-bromo-6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one(80 mg, 66.35%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=311.

Step 4: Preparation of4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

To a solution of4-bromo-6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2,7-naphthyridin-1-one(50.00 mg, 0.161 mmol, 1.00 equivalent) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(70.41 mg, 0.241 mmol, 1.50 equivalent) in dioxane (2.00 mL) and water(0.40 mL) were added K₃PO₄ (102.32 mg, 0.482 mmol, 3.00 equivalent) andPd(PPh₃)₂Cl₂ (11.28 mg, 0.016 mmol, 0.10 equivalent). After stirring for16 hours at 80° C. under a nitrogen atmosphere, the resulting mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (17:1) toafford4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(38 mg, 53.69%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=397.

Step 5: Preparation of3-[5-[(7-[[1-([4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

To a stirred mixture of4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde(80.00 mg, 0.202 mmol, 1.00 equivalent) and3-(1-oxo-5-[[7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]oxy]-3H-isoindol-2-yl)piperidine-2,6-dione(96.98 mg, 0.202 mmol, 1.00 equivalent) in DMF (1.00 mL) was addedNaBH(OAc)₃ (85.54 mg, 0.404 mmol, 2.00 equivalent) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 2 hoursat room temperature under nitrogen atmosphere. The crude product waspurified by Prep-HPLC with the following conditions (Column: Xselect CSHF-Phenyl OBD Column 19*150 mm 5 μm; Mobile Phase A: Water (0.05% TFA);Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 12 B to 24 B in 12min; 254/220 nm; RT1:9.07 min) to afford3-[5-[(7-[[1-([4-[6-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl]-7-azaspiro[3.5]nonan-2-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (73.3 mg,41.60%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J=0.7Hz, 1H), 7.89 (d, J=2.9 Hz, 1H), 7.70-7.61 (m, 2H), 7.06 (d, J=2.2 Hz,1H), 6.98 (dd, J=8.4, 2.3 Hz, 1H), 6.91 (s, 2H), 5.05 (dd, J=13.2, 5.1Hz, 1H), 4.87 (q, J=6.5 Hz, 1H), 4.43-4.32 (m, 2H), 4.26 (d, J=13.6 Hz,2H), 3.91 (s, 6H), 3.55 (s, 3H), 3.45 (d, J=12.0 Hz, 2H), 3.37 (s, 4H),3.23-3.14 (m, 1H), 3.10-2.83 (m, 6H), 2.61 (d, J=16.6 Hz, 2H), 2.45-2.33(m, 2H), 2.08 (d, J=11.8 Hz, 1H), 1.87 (d, J=28.7 Hz, 9H), 1.55-1.41 (m,2H), 1.27 (s, 6H). LCMS (ESI) m/z: [M+H]+=861.

Example 67—Preparation of3-(6-[7-[(1[[2,6-dimethoxy-4-(6-methoxy-2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

Step 1: Preparation of 6-methoxy-2-methyl-2,7-naphthyridin-1-one

A mixture of 6-chloro-2-methyl-2,7-naphthyridin-1-one (1.00 g, 5.138mmol, 1.00 equiv) and KOH (0.43 g, 7.707 mmol, 1.50 equiv) in MeOH(10.00 mL) was stirred for 4 hours at 70° C. under nitrogen atmosphere.The resulting mixture was diluted with 100 mL of water. The resultingmixture was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (10:1) to afford 6-methoxy-2-methyl-2,7-naphthyridin-1-one(800 mg, 81.86%) as a white solid. LCMS (ESI) m/z: [M+H]+=191.

Step 2: Preparation of 4-bromo-6-methoxy-2-methyl-2,7-naphthyridin-1-one

A mixture of 6-methoxy-2-methyl-2,7-naphthyridin-1-one (800.00 mg, 4.206mmol, 1.00 equiv) and NBS (898.33 mg, 5.047 mmol, 1.20 equiv) in DMF(10.00 mL) was stirred for 2 hours at 90° C. under nitrogen atmosphere.The resulting mixture was diluted with 100 mL of water. The resultingmixture was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (10:1) to afford4-bromo-6-methoxy-2-methyl-2,7-naphthyridin-1-one (600 mg, 53.01%) as awhite solid. LCMS (ESI) m/z: [M+H]⁺=269.

Step 3: Preparation of tert-butyl4-[3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxoquinazolin-6-yl]piperazine-1-carboxylate

A mixture of 4-bromo-6-methoxy-2-methyl-2,7-naphthyridin-1-one (600.00mg, 2.230 mmol, 1.00 equiv), 4-boranyl-2,6-dimethoxybenzaldehyde (396.86mg, 2.230 mmol, 1.00 equiv), Pd(dppf)Cl₂ (163.15 mg, 0.223 mmol, 0.10equiv) and Cs₂CO₃ (1452.94 mg, 4.459 mmol, 2.00 equiv) in DMF (10.00 mL)was stirred for 4 hours at 70° C. under nitrogen atmosphere. Theresulting mixture was diluted with 100 mL of water, the resultingmixture was extracted with EtOAc (2×100 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (10:1) to afford2,6-dimethoxy-4-(6-methoxy-2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(100 mg, 12.66%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=355.

Step 4: Preparation of3-(6-[7-[(1-[[2,6-dimethoxy-4-(6-methoxy-2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

A mixture of2,6-dimethoxy-4-(6-methoxy-2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(80.00 mg, 0.226 mmol, 1.00 equiv),3-[6-[7-(azetidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione(98.78 mg, 0.226 mmol, 1.00 equiv) and NaBH(AcO)₃ (95.69 mg, 0.452 mmol,2.00 equiv) in DMF (2.00 mL) was stirred for 3 hours at roomtemperature. Without any additional work-up, the mixture was purified byPrep-HPLC with the following conditions (Column: XSelect CSH Prep C18OBD Column 5 um, 19*150 mm; Mobile Phase A: Water (0.05% FA), MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 13 B to 20 B in 15 min;254/220 nm; RT1:13.18-14 min) to afford3-(6-[7-[(1[[2,6-dimethoxy-4-(6-methoxy-2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione(11.8 mg, 6.74%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.25(s, 1H), 7.57 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 6.96-6.72 (m, 5H), 5.14(dd, J=13.2, 5.1 Hz, 1H), 4.55 (s, 2H), 4.49-4.30 (m, 4H), 4.27-4.07 (m,2H), 3.99 (d, J=9.8 Hz, 9H), 3.78 (s, 4H), 3.64 (s, 3H), 3.59-3.48 (m,5H), 3.27-3.01 (m, 2H), 3.00-2.69 (m, 2H), 2.50 (dd, J=13.1, 4.8 Hz,1H), 2.35-2.00 (m, 5H). LCMS (ESI) m/z: [M+H]⁺=776.

Example 68—BRD9 Bromodomain TR-FRET Competition Binding Assay

This example demonstrates the ability of the compounds of the disclosureto biochemically inhibit BRD9 bromodomain in a competition bindingassay.

Procedure:

His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M2; SEQ ID NO:1mgsshhhhhhenlyfq/gdykddddkgslevlfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMIIKHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) wascloned, expressed, purified, and then treated with TEV protease. CleavedHis tag was removed by purification. The binding of a biotinylated smallmolecule ligand of BRD9 was assessed via the LANCE® TR-FRET platform(PerkinElmer), and the compounds were assayed for inhibitory activityagainst this interaction.

Results:

A mixture of biotinylated-ligand and SureLight™Allophycocyanin-Streptavidin (APC-SA, PerkinElmer AD0201) in 50 mM HEPES(pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01%(w/v) bovine serum albumin was added to a white 384-well PerkinElmerProxiplate Plus plate. DMSO or 3-fold serially diluted compounds werethen added to the Proxiplate followed by addition of Flag-BRD9. After a10-minute incubation at room temperature, Eu-W1024 anti-FLAG(PerkinElmer, AD0273) was added. The final reaction mixture thatcontained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight™Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG wasincubated at room temperature for 90 minutes.

The plates were then read on a PerkinElmer Envision plate reader todetermine the ratio of emission at 665 nm over 615 nm. Data wasnormalized to a DMSO control (100%) and a no protein control (0%) andthen fit to a four parameter, non-linear curve fit to calculate an IC₅₀(μM) as shown in Table 5. As shown by the results in Table 5, a numberof compounds of the present disclosure exhibit an IC₅₀ value of <1 μMfor BRD9 binding, indicating their affinity for targeting BRD9.

TABLE 5 Bromodomain TR-FRET Binding Bromodomain Compound No. TR-FRETBRD9 IC₅₀ (nM) B1 ++++ B2 ++++ B3 +++ B4 +++ B5 +++ B6 +++ D1 ++++ D2++++ D3 ++++ D4 ++++ D5 +++ D6 +++ D7 ++++ D8 +++ D9 ++ D10 +++ D11 +++D12 ++++ D13 ++ D14 +++ D15 ++++ D16 ++++ D17 +++ D18 ++++ D19 ++++ D20++++ D21 ++++ D22 +++ D23 ++++ D24 +++ D25 + D26 +++ D27 ++++ D28 ++++D29 ++++ D30 ++++ D31 +++ “+” indicates inhibitory effect of ≥ 1000 nM;“++” indicates inhibitory effect of ≥ 100 nM; “+++” indicates inhibitoryeffect of ≥ 10 nM; “++++” indicates inhibitory effect of < 10 nM; “NT”indicates not tested

Example 69—SYO1 BRD9 NanoLuc Degradation Assay

This example demonstrates the ability of the compounds of the disclosureto degrade a Nanoluciferase-BRD9 fusion protein in a cell-baseddegradation assay.

Procedure:

A stable SYO-1 cell line expressing 3×FLAG-NLuc-BRD9 was generated. Onday 0 cells were seeded in 30 μL media into each well of 384-well cellculture plates. The seeding density was 8000 cells/well. On day 1, cellswere treated with 30 nL DMSO or 30 nL of 3-fold serially DMSO-dilutedcompounds (10 points in duplicates with 1 μM as final top dose).Subsequently plates were incubated for 6 hours in a standard tissueculture incubator and equilibrated at room temperature for 15 minutes.Nanoluciferase activity was measured by adding 15 μL of freshly preparedNano-Glo Luciferase Assay Reagent (Promega N1130), shaking the platesfor 10 minutes and reading the bioluminescence using an EnVision reader.

Results:

The Inhibition % was calculated using the following formula: %Inhibition=100×(Lum_(HC)−Lum_(sample))/(Lum_(HC)−Lum_(LC)). DMSO treatedcells are employed as High Control (HC) and 1 μM of a known BRD9degrader standard treated cells are employed as Low Control (LC). Thedata was fit to a four parameter, non-linear curve fit to calculate IC₅₀(μM) values as shown in Table 6A, Table 6B, and Table 6C. As shown bythe results in Table 6A, Table 6B, and Table 6C, a number of compoundsof the present disclosure exhibit an IC₅₀ value of <1 μM for thedegradation of BRD9, indicating their use as compounds for reducing thelevels and/or activity of BRD9 and their potential for treatingBRD9-related disorders.

TABLE 6A SYO1 BRD9-NanoLuc Degradation SYO1 BRD9-NanoLuc Compound No.degradation IC₅₀ (nM) D1 ++++ D2 ++ D3 +++ D4 ++ D5 ++ D6 +++ D7 ++++ D8+++ D9 + D10 +++ D11 ++ D12 +++ D13 + D14 ++ D15 ++++ D16 ++++ D17 ++++D18 ++++ D19 ++++ D20 ++++ D21 ++++ D22 ++ D23 ++++ D24 +++ D25 ++ D26+++ D27 ++++ D28 ++++ D29 ++++ D30 ++++ D31 ++ “+” indicates inhibitoryeffect of ≥ 1000 nM; “++” indicates inhibitory effect of ≥ 100 nM; “+++”indicates inhibitory effect of ≥ 10 nM; “++++” indicates inhibitoryeffect of < 10 nM; “NT” indicates not tested

TABLE 6B SYO1 BRD9-NanoLuc Degradation SYO1 BRD9-NanoLuc Compound No.degradation IC₅₀ (nM) D32 ++++ D33 ++++ D34 ++++ D35 ++++ D36 ++++ D37++++ D38 ++++ D39 ++++ D40 ++++ D41 ++++ D42 ++++ D43 + D44 +++ D45 ++D46 ++++ D47 +++ D48 ++++ D49 ++++ D50 ++++ D51 ++++ D52 ++++ D53 ++++D54 ++++ D55 ++++ D56 ++++ D57 ++++ D58 ++++ D59 ++++ D60 ++++ D61 ++++D62 ++++ D63 ++++ D64 ++ D65 ++++ D66 ++++ D67 ++++ D68 ++++ D69 ++++D70 ++++ D71 ++++ D72 ++++ D73 ++++ D74 +++ D75 ++++ D76 ++++ D77 ++++D78 ++++ D79 ++++ D80 ++++ D81 ++++ D82 ++++ D83 ++++ D84 +++ D85 ++++D86 ++++ D87 ++++ D88 +++ D89 ++++ D90 ++++ D91 ++++ D92 ++++ D93 ++++D94 +++ D95 ++++ D96 ++++ D97 ++++ D98 ++++ D99 ++++ D100 ++++ D101 ++++D102 ++++ D103 ++++ D104 ++++ D105 ++++ D106 ++++ D107 ++++ D108 ++++D109 ++++ D110 ++++ D111 ++++ D112 ++++ D113 ++++ D114 ++++ D115 ++++D116 ++++ D117 +++ D118 ++++ D119 +++ D120 ++++ D121 ++++ D122 ++++ D123++++ D124 ++++ D125 ++++ D126 ++++ D127 ++++ D128 ++++ D129 ++++ D130++++ D131 ++++ D132 ++++ D133 ++++ D134 ++++ D135 ++++ D136 ++++ D137++++ D138 ++++ D139 ++++ D140 ++++ D141 ++++ D142 ++++ D143 ++++ D144++++ D145 ++++ D146 ++++ D147 ++++ D148 ++++ D149 ++++ D150 ++++ D151++++ D152 ++++ D153 ++++ D154 ++++ D155 ++++ D156 ++++ D157 ++++ D158++++ D159 ++++ D160 ++++ D161 ++++ D162 ++++ D163 ++++ D164 ++++ D165+++ D166 ++++ D167 ++++ D168 ++++ D169 +++ D170 ++++ D171 ++++ D172 +++D173 ++++ D174 ++++ D175 + D176 ++++ D177 ++++ D178 ++++ D179 + D180++++ D181 + D182 ++++ D183 + D184 ++++ “+” indicates inhibitory effectof ≥ 1000 nM; “++” indicates inhibitory effect of ≥ 100 nM; “+++”indicates inhibitory effect of ≥ 10 nM; “++++” indicates inhibitoryeffect of < 10 nM; “NT” indicates not tested

TABLE 6C SYO1 BRD9-NanoLuc Degradation SYO1 BRD9-NanoLuc Compound No.degradation IC₅₀ (nM) D185 ++++ D186 ++++ D187 ++++ D188 ++++ D189 ++++D190 ++++ D191 ++ D192 ++++ D193 ++++ D194 ++++ D195 ++++ D196 ++++ D197++++ D198 ++++ D199 ++++ D200 ++++ D201 ++++ D202 ++++ D203 ++++ D204++++ D205 +++ D206 ++++ D207 ++++ D208 ++++ D209 ++++ D210 ++++ D211++++ D212 ++++ D213 ++++ D214 ++++ D215 ++++ D216 ++++ D217 ++++ D218++++ D219 ++++ D220 ++++ D221 ++++ D222 ++++ D223 ++++ D224 ++++ D225++++ D226 ++++ D227 ++++ D228 ++++ D229 ++++ D230 ++++ D231 ++++ D232++++ D233 ++++ D234 ++++ D235 ++++ D236 ++++ D237 ++++ D238 ++++ D239++++ D240 ++++ D241 ++++ D242 ++++ D243 ++++ D244 ++++ D245 ++++ D246++++ D247 ++++ D248 ++++ D249 ++ D250 ++ D251 + D252 +++ D253 + D254++++ D255 ++++ D256 ++++ D257 ++++ D258 ++++ D259 + D260 ++++ D261 +D262 ++++ D263 ++++ D264 ++++ D265 ++++ D266 ++ D267 ++++ D268 ++++ D269++++ D270 +++ D271 ++++ D272 ++++ D273 ++++ D274 ++++ D275 ++++ D276++++ D277 ++++ D278 ++++ D279 ++++ D280 ++++ D281 ++++ D282 +++ D283 ++D284 ++++ D285 + D286 ++++ D287 ++++ D288 ++++ D289 ++++ D290 ++++ D291++++ D292 +++ D293 ++++ D294 ++++ D295 ++++ D296 ++++ D297 ++++ D298++++ D299 ++++ D300 ++++ D301 ++++ D302 ++++ D303 ++++ D304 ++++ D305++++ D306 ++++ D307 ++++ D308 ++++ D309 ++++ D310 ++++ D311 ++++ D312++++ D313 ++++ D314 ++++ D315 ++++ D316 ++++ “+” indicates inhibitoryeffect of ≥ 1000 nM; “++” indicates inhibitory effect of ≥ 100 nM; “+++”indicates inhibitory effect of ≥ 10 nM; “++++” indicates inhibitoryeffect of < 10 nM; “NT” indicates not tested

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificembodiments thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are in the claims.

1. A compound having the structure Formula I:

where R¹ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl; Z¹ is CR² or N; R² is H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl, oroptionally substituted C₂-C₉ heteroaryl; X¹ is N or CH, and X² is C—R⁷;or X¹ is C—R⁷, and X² is N or CH; R⁷ is optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted amino, optionally substitutedsulfone, optionally substituted sulfonamide, optionally substitutedcarbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclylhaving 3 to 6 atoms; X³ is N or CH; X⁴ is N or CH; G is optionallysubstituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl, ora pharmaceutically acceptable salt thereof.
 2. A compound having thestructure of Formula II:A-L-B  Formula II, wherein L is a linker; B is a degradation moiety; andA has the structure of Formula III:

wherein R¹ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl; Z¹ is CR² or N; R² is H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl, oroptionally substituted C₂-C₉ heteroaryl; X¹ is N or CH, and X² isC—R^(7″); or X¹ is C—R^(7″), and X² is N or CH; R^(7″) is

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedamino, optionally substituted sulfone, optionally substitutedsulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, oroptionally substituted heterocyclyl having 3 to 6 atoms; R^(7′) is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₁₀ carbocycylyl; X³ is N orCH; X⁴ is N or CH; G″ is

optionally substituted C₃-C₁₀ carbocyclyl, C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉heteroaryl; G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and A¹ is a bond between A and thelinker, where G″ is

or R^(7″) is

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 or 2, wherein R¹ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, or optionally substituted C₃-C₁₀ carbocyclyl.4. The compound of claim 3, wherein R¹ is H.
 5. The compound of claim 3,wherein R¹ is optionally substituted C₁-C₆ alkyl.
 6. The compound ofclaim 5, wherein R¹ is


7. The compound of claim 6, wherein R¹ is optionally substituted C₂-C₆alkenyl.
 8. The compound of claim 7, wherein R¹ is


9. The compound of claim 8, wherein R¹ is optionally substituted C₃-C₁₀carbocyclyl.
 10. The compound of claim 9, wherein R¹ is


11. The compound of claim 3, wherein R¹ is H or


12. The compound of claim 11, wherein R¹ is H.
 13. The compound of claim11, wherein R¹ is


14. The compound of any one of claims 1 to 13, wherein Z¹ is N.
 15. Thecompound of any one of claims 1 to 13, wherein Z¹ is CR².
 16. Thecompound of claim 15, wherein R² is H, halogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.
 17. The compound of claim 16, wherein R² is H,halogen, or optionally substituted C₁-C₆ alkyl.
 18. The compound ofclaim 17, wherein R² is H, F, or


19. The compound of any one of claims 2 to 18, wherein X¹ is N and X² isC—R^(7″).
 20. The compound of any one of claims 2 to 18, wherein X¹ isCH and X² is C—R^(7″).
 21. The compound of any one of claims 2 to 18,wherein X¹ is C—R^(7″) and X² is N.
 22. The compound of any one ofclaims 2 to 18, wherein X¹ is C—R^(7″) and X² is CH.
 23. The compound ofany one of claims 2 to 22, wherein R^(7″) is optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted carbocyclyl having 3 to 6 atoms, or optionally substitutedheterocyclyl having 3 to 6 atoms.
 24. The compound of claim 23, whereinR^(7″) is optionally substituted C₁-C₆ alkyl.
 25. The compound of claim24, wherein R^(7″) is


26. The compound of claim 23, wherein R^(7″) is optionally substitutedC₁-C₆ heteroalkyl.
 27. The compound of claim 23, wherein R^(7″) isoptionally substituted C₁-C₆ alkoxy or optionally substituted amino. 28.The compound of claim 26 or 27, wherein R^(7″) is —NR³R⁴ or —OR⁴, whereR³ is H or optionally substituted C₁-C₆ alkyl, and R⁴ is optionallysubstituted C₁-C₆ alky.
 29. The compound of claim 28, wherein R^(7″) is—NR³R⁴.
 30. The compound of claim 29, wherein X¹ is N and X² is C—NR³R⁴.31. The compound of claim 29, wherein X¹ is C—NR³R⁴ and X² is N.
 32. Thecompound of claim 28, wherein R⁷ is —OR⁴.
 33. The compound of claim 32,wherein X¹ is N and X² is C—OR⁴.
 34. The compound of claim 32, whereinX¹ is C—OR⁴ and X² is N.
 35. The compound of any one of claims 28 to 34,wherein R³ is H.
 36. The compound of any one of claims 28 to 35, whereinR³ is


37. The compound of any one of claims 28 to 36, wherein R⁴ is


38. The compound of claim 23, wherein R^(7″) is optionally substitutedcarbocyclyl having 3 to 6 atoms.
 39. The compound of claim 38, whereinR^(7″) is


40. The compound of claim 23, wherein R^(7″) is optionally substitutedheterocyclyl having 3 to 6 atoms.
 41. The compound of claim 40, whereinR^(7″) is


42. The compound of claim 23, wherein R^(7″) is optionally substitutedsulfone or optionally substituted sulfonamide.
 43. The compound of claim42, wherein R^(7″) is


44. The compound of any one of claims 2 to 43, wherein R^(7″) is


45. The compound of claim 44, wherein R^(7″) is


46. The compound of claim 45, wherein R^(7″) is


47. The compound of any one of claims 2 to 46, wherein G″ is


48. The compound of claim 47, wherein G′ is optionally substitutedC₆-C₁₀ arylene or optionally substituted C₂-C₉ heteroarylene.
 49. Thecompound of claim 48, wherein G′ is optionally substituted C₆-C₁₀arylene.
 50. The compound of claim 49, wherein G′ is

wherein each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1′) and R^(G2′), R^(G2′) and R^(G3′), R^(G3′)and R^(G4′), and/or R^(G4′) and R^(G5′), together with the carbon atomsto which each is attached, combine to form

and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, wherein one of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′)is A¹, or

is substituted with A¹.
 51. The compound of claim 50, wherein each ofR^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl; or R^(G1′) andR^(G2′), R^(G2′) and R^(G3′), R^(G3′) and R^(G4′), and/or R^(G4′) andR^(G5′), together with the carbon atoms to which each is attached,combine to form

and

is optionally substituted C₂-C₉ heteroaryl or optionally substitutedC₂-C₉ heterocyclyl, any of which is optionally substituted with A¹,wherein one of R^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is A¹, or

is substituted with A¹.
 52. The compound of claim 51, wherein each ofR^(G1′), R^(G2′), R^(G3′), R^(G4′), and R^(G5′) is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl.
 53. The compoundof claim 52, wherein each of R^(G1′), R^(G2′), R^(G3′), R^(G4′), andR^(G5′) is, independently, H, A¹, F, Cl,


54. The compound of claim 53, wherein each of R^(G1′), R^(G2′), R^(G3′),R^(G4′), and R^(G5′) is, independently, H, A¹, F,


55. The compound of claim 54, wherein each of R^(G1′), R^(G2′), R^(G3′),R^(G4′), and R^(G5′) is, independently, H, A¹, F, Cl,


56. The compound of claim 55, wherein R^(G3′) is A¹.
 57. The compound ofclaim 55, wherein R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is

and R^(G5′) is H.
 58. The compound of claim 55, wherein R^(G1′) is H;R^(G2′) is

R^(G3′), is A¹; R^(G4′), is H; and R^(G5′) is


59. The compound of claim 55, wherein R^(G1′) is H; R^(G2′) is

R^(G3′) is A¹; R^(G4′) is Cl or F; and R^(G5′) is H.
 60. The compound ofclaim 55, wherein R^(G1′) is H; R^(G2′) is

R^(G3′), is A¹; R^(G4′), is H; and R^(G5′) is H.
 61. The compound ofclaim 55, wherein R^(G1′) is H; R^(G2′) is

R^(G3′), is A¹; R^(G4′), is

and R^(G5′) is H.
 62. The compound of claim 51, wherein R^(G1′) andR^(G2′), R^(G2′) and R^(G3′), R^(G3′) and R^(G4′), and/or R^(G4′) andR^(G5′), together with the carbon atoms to which each is attached,combine to form

and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A¹, wherein one of R^(G1′), R^(G2′), R^(G3′), R^(G4′),and R^(G5′) is A¹, or

is substituted with A¹.
 63. The compound of claim 51, wherein R^(G1′)and R^(G2′), R^(G2′) and R^(G3′), R^(G3′) and R^(G4′), and/or R^(G4′)and R^(G5′), together with the carbon atoms to which each is attached,combine to form

and

is optionally substituted C₂-C₉ heteroaryl, which is optionallysubstituted with A¹, wherein one of R^(G1′), R^(G2′), R^(G3′), R^(G4′),and R^(G5′) is A¹, or

is substituted with A¹.
 64. The compound of claim 62, wherein G′ is

wherein R^(G6′) is H, A¹, or optionally substituted C₁-C₆ alkyl.
 65. Thecompound of claim 63, wherein G′ is

wherein R^(G6′) is H, A¹, or optionally substituted C₁-C₆ alkyl
 66. Thecompound of claim 64 or 65, wherein R^(G6′) is H, A¹, or


67. The compound of claim 66, wherein R^(G6′) is H.
 68. The compound ofclaim 48, wherein G′ is optionally substituted C₂-C₉ heteroarylene. 69.The compound of claim 68, wherein G′ is

wherein each of R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7′) and R^(G8′), R^(G8′) and R^(G9′), R^(G9′)and R^(G10′), and/or R^(G10′) and R^(G11′), together with the carbonatoms to which each is attached, combine to form

and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, whereinone of R^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is A¹; or

is substituted with A¹.
 70. The compound of claim 69, wherein each ofR^(G7′), R^(G8′), R^(G9′), R^(G10′), and R^(G11′) is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl.
 71. The compoundof claim 69 or 70, wherein G′ is


72. The compound of any one of claims 69 to 71, wherein R^(G7′) is H;R^(G8′) is

is A¹; and R^(G11′) is H.
 73. The compound of claim 68, wherein G′ is

wherein each of R^(G12′), R^(G13′), and R^(G14′) is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12′) and R^(G14′), together with the carbon atoms to which each isattached, combine to form

and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, wherein one of R^(G12′), R^(G13′), and R^(G14′) is A¹; or

is substituted with A¹.
 74. The compound of any one of claims 2 to 22,wherein R^(7″) is


75. The compound of claim 74, wherein G″ is optionally substitutedC₆-C₁₀ aryl or optionally substituted C₂-C₉ heteroaryl.
 76. The compoundof claim 75, wherein G″ is optionally substituted C₆-C₁₀ aryl.
 77. Thecompound of claim 76, wherein G″ is

wherein each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.
 78. Thecompound of claim 77, wherein each of R^(G1), R^(G2), R^(G3), R^(G4),and R^(G5) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.
 79. Thecompound of claim 78, wherein each of R^(G1), R^(G2), R^(G3), R^(G4),and R^(G5) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.
 80. The compound of claim 79, wherein each of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H, F, Cl,


81. The compound of claim 80, wherein each of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is, independently, H, F,


82. The compound of claim 81, wherein each of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is, independently, H, F, Cl,


83. The compound of claim 82, wherein two or more of R^(G1), R^(G2),R^(G3), R^(G4), and R^(G5) is H.
 84. The compound of claim 83, whereinR^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H.
 85. The compound of claim 83, wherein R^(G1) is H;R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is


86. The compound of claim 83, wherein R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is Cl or F; and R^(G5) is H.
 87. The compound of claim 83,wherein R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is H.
 88. The compound of claim 83, whereinR^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H.
 89. The compound of claim 78, wherein R^(G1) andR^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4) and R^(G5),together with the carbon atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl.
 90. The compound ofclaim 78, wherein R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl.
 91. The compound of claim 89, wherein G″ is

wherein R^(G6) is H or optionally substituted C₁-C₆ alkyl.
 92. Thecompound of claim 90, wherein G″ is

wherein R^(G6) is H or optionally substituted C₁-C₆ alkyl.
 93. Thecompound of claim 91 or 92, wherein R^(G6) is H or


94. The compound of claim 93, wherein R^(G6) is H.
 95. The compound ofclaim 75, wherein G″ is optionally substituted C₂-C₉ heteroaryl.
 96. Thecompound of claim 95, wherein G″ is

wherein each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.
 97. The compound of claim 96,wherein each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.
 98. The compound of claim 96 or 97, wherein G″ is


99. The compound of claim 98, wherein R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.
 100. The compound of claim 89, wherein G″is

wherein each of R^(G12), R^(G13), and R^(G14) is, independently, H,halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.
 101. The compound of anyone of claims 74 to 100, wherein R^(7′) is H, optionally substitutedC₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocycylyl.
 102. Thecompound of claim 101, wherein R^(7′) is H or optionally substitutedC₁-C₆ alkyl.
 103. The compound of claim 102, wherein R^(7′) is H,


104. The compound of claim 103, wherein R^(7′) is H or


105. The compound of claim 104, wherein R^(7′) is H.
 106. The compoundof claim 104, wherein R^(7′) is


107. The compound of any one of claims 2 to 106, wherein A has thestructure of Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 108. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIc:

or a pharmaceutically acceptable salt thereof.
 109. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIe:

or a pharmaceutically acceptable salt thereof.
 110. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIf:

or a pharmaceutically acceptable salt thereof.
 111. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIg:

or a pharmaceutically acceptable salt thereof.
 112. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIh:

or a pharmaceutically acceptable salt thereof.
 113. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIj:

or a pharmaceutically acceptable salt thereof.
 114. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIn:

or a pharmaceutically acceptable salt thereof.
 115. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIo:

or a pharmaceutically acceptable salt thereof.
 116. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIs:

or a pharmaceutically acceptable salt thereof.
 117. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIu:

or a pharmaceutically acceptable salt thereof.
 118. The compound of anyone of claims 2 to 106, wherein A has the structure of Formula IIIv:

or a pharmaceutically acceptable salt thereof.
 119. The compound of anyone of claims 2 to 118, wherein the degradation moiety is a ubiquitinligase binding moiety.
 120. The compound of claim 119, wherein theubiquitin ligase binding moiety comprises Cereblon ligands, IAP(Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2),or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.121. The compound of claim 119 or 120, wherein the degradation moietycomprises the structure of Formula Y:

where A² is a bond between the degradation moiety and the linker; v1 is0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; T¹ is a bond or

T² is

R^(5A) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; each R^(J1) is, independently, halogen,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl; J^(A) is absent, O, optionally substituted amino,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl; and J is absent, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₆-C₁₀ arylene, optionallysubstituted C₂-C₉ heterocyclylene, or optionally substituted C₂-C₉heteroarylene, or a pharmaceutically acceptable salt thereof.
 122. Thecompound of claim 121, wherein T² is


123. The compound of claim 122, wherein T² is


124. The compound of claim 122, wherein T² is


125. The compound of any one of claims 121 to 124, wherein the structureof Formula Y has the structure of Formula Y1:

or a pharmaceutically acceptable salt thereof.
 126. The compound ofclaim 125, wherein T¹ is a bond.
 127. The compound of claim 125, whereinT¹ is


128. The compound of any one of claims 121 to 127, wherein the structureof Formula Y has the structure of Formula Y2:

or a pharmaceutically acceptable salt thereof.
 129. The compound of anyone of claims 121 to 127, wherein the structure of Formula Y has thestructure of Formula Z:

or a pharmaceutically acceptable salt thereof.
 130. The compound of anyone of claims 121 to 129, wherein u1 is
 2. 131. The compound of claim130, wherein the structure of Formula Z has the structure of FormulaAA0:

or a pharmaceutically acceptable salt thereof.
 132. The compound of anyone of claims 121 to 129, wherein u1 is
 1. 133. The compound of claim132, wherein the structure of Formula Z has the structure of Formula AB:

or a pharmaceutically acceptable salt thereof.
 134. The compound of anyone of claims 121 to 129, wherein u1 is
 3. 135. The compound of claim134, wherein the structure of Formula Z has the structure of Formula AC:

or a pharmaceutically acceptable salt thereof.
 136. The compound of anyone of claims 121 to 135, wherein J^(A) is absent.
 137. The compound ofany one of claims 121 to 135, wherein J^(A) is optionally substitutedC₁-C₆ alkyl.
 138. The compound of claim 137, wherein J^(A) is


139. The compound of claim 138, wherein the structure of Formula AA0 hasthe structure of Formula AA0:

or a pharmaceutically acceptable salt thereof.
 140. The compound of anyone of claims 121 to 139, wherein v1 is 0, 1, 2, or
 3. 141. The compoundof claim 140, wherein v1 is
 0. 142. The compound of claim 141, whereinthe structure of Formula AA has the structure of Formula AA1:

or a pharmaceutically acceptable salt thereof.
 143. The compound of anyone of claims 121 to 142, wherein R^(A5) is H or optionally substitutedC₁-C₆ alkyl.
 144. The compound of claim 143, wherein R^(A5) is H. 145.The compound of claim 143, wherein R^(A5) is methyl.
 146. The compoundof any one of claims 121 to 142, wherein R^(A5) is optionallysubstituted C₁-C₆ heteroalkyl.
 147. The compound of claim 146, whereinR^(A5) is


148. The compound of claim 139, wherein the structure of Formula AA hasthe structure of Formula AA1:

or a pharmaceutically acceptable salt thereof.
 149. The compound ofclaim 133, wherein the structure of Formula AB has the structure ofFormula AB1:

or a pharmaceutically acceptable salt thereof.
 150. The compound ofclaim 135, wherein the structure of Formula AC has the structure ofFormula AC1:

or a pharmaceutically acceptable salt thereof.
 151. The compound of anyone of claims 121 to 150, wherein J is absent.
 152. The compound ofclaim 151, wherein the structure of Formula AA1 has the structure ofFormula AA2:

or a pharmaceutically acceptable salt thereof.
 153. The compound of anyone of claims 121 to 150, wherein J is optionally substituted C₃-C₁₀carbocyclylene or optionally substituted C₆-C₁₀ arylene.
 154. Thecompound of claim 153, wherein the structure of Formula AA has thestructure of Formula AA4:

or a pharmaceutically acceptable salt thereof.
 155. The compound of anyone of claims 121 to 150, wherein J is optionally substituted C₂-C₉heterocyclylene or optionally substituted C₂-C₉ heteroarylene.
 156. Thecompound of claim 155, wherein the structure of Formula AA has thestructure of Formula AA3:

or a pharmaceutically acceptable salt thereof.
 157. The compound ofclaim 155, wherein the structure of Formula AA has the structure ofFormula A:

wherein in Y¹ is

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; R^(A6) is H or optionally substitutedC₁-C₆ alkyl; and R^(A7) is H or optionally substituted C₁-C₆ alkyl; orR^(A6) and R^(A7), together with the carbon atom to which each is bound,combine to form optionally substituted C₃-C₈ carbocyclyl or optionallysubstituted C₂-C₅ heterocyclyl; or R^(A6) and R^(A7), together with thecarbon atom to which each is bound, combine to form optionallysubstituted C₃-C₈ carbocyclyl or optionally substituted C₂-C₅heterocyclyl; R^(A8) is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; each of R^(A1), R^(A2), R^(A3)and R^(A4) is, independently, H, A², halogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4), together withthe carbon atoms to which each is attached, combine to form

and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.158. The compound of claim 157, each of R^(A1), R^(A2), R^(A3), andR^(A4) is, independently, H, A², halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4),together with the carbon atoms to which each is attached, combine toform

and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.159. The compound of claim 158, wherein each of R^(A1), R^(A2), R^(A3),and R^(A4) is, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, hydroxyl, optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), together with thecarbon atoms to which each is attached, combine to form

and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 160. The compound of claim 159, wherein each ofR^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 161. The compound of any one of claims 157 to160, wherein Y¹ is


162. The compound of claim 161, wherein Y¹ is


163. The compound of claim 161, wherein Y¹ is


164. The compound of claim 163, wherein Y¹ is


165. The compound of claim 164, wherein Y¹ is


166. The compound of any one of claims 157 to 165, wherein the structureof Formula A has the structure of Formula A1:

or a pharmaceutically acceptable salt thereof.
 167. The compound of anyone of claims 157 to 165 wherein the structure of Formula A has thestructure of Formula A2:

or a pharmaceutically acceptable salt thereof.
 168. The compound of anyone of claims 157 to 165, wherein the structure of Formula A has thestructure of Formula A3:

or a pharmaceutically acceptable salt thereof.
 169. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A4:

or a pharmaceutically acceptable salt thereof.
 170. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A5:

or a pharmaceutically acceptable salt thereof.
 171. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A6:

or a pharmaceutically acceptable salt thereof.
 172. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A7:

or a pharmaceutically acceptable salt thereof.
 173. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A8:

or a pharmaceutically acceptable salt thereof.
 174. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A9:

or a pharmaceutically acceptable salt thereof.
 175. The compound of anyone of claims 157 to 167, wherein the structure of Formula A has thestructure of Formula A10:

or a pharmaceutically acceptable salt thereof.
 176. The compound of anyone of claims 157 to 175, wherein the structure of Formula A is

or derivative or analog thereof.
 177. The compound of claim 176, whereinthe structure of Formula A is


178. The compound of claim 177, wherein the structure of Formula A is

or derivative or analog thereof.
 179. The compound of any one of claims157 to 175, wherein

wherein R^(A9) is H, A², optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl.
 180. The compound of claim179, wherein the structure of Formula A is


181. The compound of claim 180, wherein R^(A9) is H.
 182. The compoundof claim 180, wherein R^(A9) is A².
 183. The compound of claim 182,wherein the structure of Formula A is


184. The compound of claim 155, wherein the structure of Formula AA hasthe structure of Formula B:

wherein R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; each of R^(A1), R^(A2), R^(A3), andR^(A4) is, independently, H, A², halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and A⁴, together with thecarbon atoms to which each is attached, combine to form

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.185. The compound of claim 184, wherein each of R^(A1), R^(A2), R^(A3),and R^(A4) is, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, hydroxyl, optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), together with thecarbon atoms to which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 186. The compound of claim 185, wherein each ofR^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 187. The compound of any one of claims 184 to186, wherein the structure of Formula B has the structure of Formula B1:

or a pharmaceutically acceptable salt thereof.
 188. The compound of anyone of claims 184 to 186, wherein the structure of Formula B has thestructure of Formula B2:

or a pharmaceutically acceptable salt thereof.
 189. The compound of anyone of claims 184 to 186, wherein the structure of Formula B has thestructure of Formula B3:

or a pharmaceutically acceptable salt thereof.
 190. The compound of anyone of claims 184 to 186, wherein the structure of Formula B has thestructure of Formula B4:

or a pharmaceutically acceptable salt thereof.
 191. The compound of anyone of claims 184 to 186, wherein the structure of Formula B is


192. The compound of any one of claims 2 to 118, wherein the degradationmoiety comprises the structure of Formula C:

wherein R^(B1) is H, A², optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; R^(B2) is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;R^(B3) is A², optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl; R^(B4)is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substituted C₁-C₆ alkylC₆-C₁₀ aryl; R^(B5) is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; v2 is 0, 1, 2, 3, or 4; eachR^(B6) is, independently, halogen, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and eachof R^(B7) and R^(B8) is, independently, H, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₆-C₁₀ aryl, whereinone of R^(B1) and R^(B3) is A², or a pharmaceutically acceptable saltthereof.
 193. The compound of claim 192, wherein the structure ofFormula C is

or derivative or analog thereof.
 194. The compound of any one of claims2 to 118, wherein the degradation moiety comprises the structure ofFormula D:

wherein A² is a bond between B and the linker; each of R^(C1), R^(C2),and R^(C7) is, independently, H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; R^(C3) is optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkylC₃-C₁₀ carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;R^(C5) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl; v3 is 0, 1, 2, 3, or 4; each R^(C8) is,independently, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v4 is 0,1, 2, 3, or 4; and each R^(C9) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino, or a pharmaceutically acceptable salt thereof. 195.The compound of claim 194, wherein the structure of Formula D is

or derivative or analog thereof.
 196. The compound of any one of claims2 to 118, wherein the degradation moiety comprises the structure ofFormula E:

wherein A² is a bond between B and the linker; each of R^(C10) andR^(C11) is, independently, H, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, oroptionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl; v5 is 0, 1, 2, 3, or 4;each R^(C12) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v6is 0, 1, 2, 3, or 4; and each R²¹ is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino, or a pharmaceutically acceptable salt thereof. 197.The compound of claim 196, wherein the structure of Formula E is

or derivative or analog thereof.
 198. The compound of any one of claims2 to 118, wherein the degradation moiety comprises the structure ofFormula FA:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

=is a single bond or a double bond; u2 is 0, 1, 2, or 3; A² is a bondbetween the degrader and the linker; Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S,C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl,P(O)OH, P(O)NH₂; Y^(Fb) is NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O,or S; Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂; each of R^(Fb),R^(Fc), R^(Fd), and R^(Fe) is, independently, H, alkyl, aliphatic,heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino,—NHalkyl, or —NaIkyl₂; or R^(Fb) and R^(Fc), together with the carbonatom to which each is attached, combine to form a 3-, 4-, 5-, or6-membered spirocarbocyclylene, or a 4-, 5-, or 6-memberedspiroheterocyclylene comprising 1 or 2 heteroatoms selected from N andO; or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; and or R^(Fd) andR^(Fb), together with the carbon atoms to which each is attached,combine to form a 1, 2, 3, or 4 carbon bridged ring; each of Y^(Fd) andY^(F1) is, independently, CH₂, CHR^(FF2), C(R^(FF2))₂, C(O), N, NH,NR^(FF3), O, S, or S(O); Y^(Fe) is a bond or a divalent moiety attachedto Y^(Fd) and Y^(Ff) that contains 1 to 5 contiguous carbon atoms thatform a 3 to 8-membered ring, wherein 1, 2, or 3 carbon atoms can bereplaced with a nitrogen, oxygen, or sulfur atom; wherein one of thering atoms is substituted with A² and the others are substituted withone or more groups independently selected from H and R^(FF1); andwherein the contiguous atoms of Y^(Fe) can be attached through a singleor double bond; each R^(FF1) is, independently, H, alkyl, alkenyl,alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino,alkylhydroxyl, or haloalkyl; each R^(FF2) is, independently, alkyl,alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H,—C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, includingalkyl), —NH(aliphatic, including alkyl), —N(aliphatic includingalkyl)(aliphatic including alkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl,—NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, aliphatic, heteroaliphatic, aryl,heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH,—Salkyl, or haloalkyl; and R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H,—C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y^(Fd) or Y^(Ff) issubstituted with A², then Y^(Fe) is a bond, or a pharmaceuticallyacceptable salt thereof.
 199. The compound of any one of claims 2 to118, wherein the degradation moiety comprises the structure of FormulaFB:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo; A²is a bond between the degrader and the linker; Y^(Fa) is CR^(Fb)R^(Fe),C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,P(O)alkyl, P(O)OH, P(O)NH₂; each of Y^(Fb) and Y^(Fg) is, independently,NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))², O, or S; Y^(Fc) isCR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂; each of R^(Fb), R^(Fc),R^(Fd), R^(Fe), R^(Ff), and R_(Fg) is, independently, H, alkyl,aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl,alkoxy, amino, —NHalkyl, or —NaIkyl₂; or R^(Fb) and R^(Fc), togetherwith the carbon atom to which each is attached, combine to form a 3-,4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-memberedspiroheterocyclylene comprising 1 or 2 heteroatoms selected from N andO; or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; or R^(Ff) andR^(Fg), together with the carbon atom to which each is attached, combineto form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selectedfrom N and O; or R^(Fd) and R^(Fb), together with the carbon atoms towhich each is attached, combine to form a 1, 2, 3, or 4 carbon bridgedring; or R^(Fd) and R^(Ff), together with the carbon atoms to which eachis attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; orR^(Fb) and R^(Fg), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring; each ofY^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2), C(R^(FF2))₂, C(O),N, NH, NR^(FF3), O, S, or S(O); Y^(Fe) is a bond or a divalent moietyattached to Y^(Fd) and Y^(Ff) that contains 1 to 5 contiguous carbonatoms that form a 3 to 8-membered ring, wherein 1, 2, or 3 carbon atomscan be replaced with a nitrogen, oxygen, or sulfur atom; wherein one ofthe ring atoms is substituted with A² and the others are substitutedwith one or more groups independently selected from H and R^(FF1); andwherein the contiguous atoms of Y^(Fe) can be attached through a singleor double bond; each R^(FF1) is, independently, H, alkyl, alkenyl,alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino,alkylhydroxyl, or haloalkyl; each R^(FF2) is, independently, alkyl,alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H,—C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, includingalkyl), —NH(aliphatic, including alkyl), —N(aliphatic includingalkyl)(aliphatic including alkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl,—NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, aliphatic, heteroaliphatic, aryl,heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH,—Salkyl, or haloalkyl; and R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H,—C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y^(Fd) or Y^(Ff) issubstituted with A², then Y^(Fe) is a bond, or a pharmaceuticallyacceptable salt thereof.
 200. The compound of any one of claims 2 to118, wherein the degradation moiety comprises the structure of FormulaF1:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 201. Thecompound of any one of claims 2 to 118, wherein the degradation moietycomprises the structure of Formula F2:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 202. Thecompound of any one of claims 2 to 118, wherein the degradation moietycomprises the structure of Formula G:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 203. Thecompound of any one of claims 2 to 202, wherein the linker has thestructure of Formula IV:A¹-(B¹)_(f)—(C¹)_(g)—(B²)_(h)-(D)-(B³)_(i)—(C²)_(j)—(B⁴)_(k)-A²  FormulaIV wherein A¹ is a bond between the linker and A; A² is a bond between Band the linker; each of B¹, B², B³, and B⁴ is, independently, optionallysubstituted C₁-C₂ alkyl, optionally substituted C₁-C₃ heteroalkyl, O, S,S(O)₂, or NR^(N); each R^(N) is, independently, H, optionallysubstituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionallysubstituted C₂₋₄ alkynyl, optionally substituted C₂₋₆ heterocyclyl,optionally substituted C₆₋₁₂ aryl, or optionally substituted C₁₋₇heteroalkyl; each of C¹ and C² is, independently, carbonyl,thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is,independently, 0 or 1; and D is optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, optionally substituted C₂-C₁₀ polyethyleneglycol, or optionally substituted C₁₋₁₀ heteroalkyl, or a chemical bondlinking A¹-(B′)_(f)—(C¹)_(g)—(B²)_(h)— to—(B³)_(i)—(C²)_(j)—(B⁴)_(k)-A².
 204. The compound of claim 203, whereineach of B¹, B², B³, and B⁴ is, independently, optionally substitutedC₁-C₄ alkyl, optionally substituted C₁-C₄ heteroalkyl, or NR^(N). 205.The compound of claim 202 or 203, wherein each R^(N) is, independently,H or optionally substituted C₁-C₄ alkyl.
 206. The compound of any one ofclaims 202 to 205, wherein each R^(N) is, independently, H or methyl.207. The compound of any one of claims 203 to 206, wherein each of B¹and B⁴ is, independently,


208. The compound of claim 207 wherein B¹ is


209. The compound of any one of claims 203 to 208, wherein each of C¹and C² is, independently,


210. The compound of claim 209, wherein C¹ is


211. The compound of any one of claims 203 to 210, wherein B² is NR^(N).212. The compound of any one of claims 203 to 210, wherein B² isoptionally substituted C₁-C₄ alkyl.
 213. The compound of any one ofclaims 203 to 212, wherein f is
 0. 214. The compound of any one ofclaims 203 to 212, wherein f is
 1. 215. The compound of any one ofclaims 203 to 214, wherein g is
 1. 216. The compound of any one ofclaims 203 to 215, wherein h is
 0. 217. The compound of any one ofclaims 203 to 215, wherein h is
 1. 218. The compound of any one ofclaims 203 to 217, wherein i is
 0. 219. The compound of any one ofclaims 203 to 218, wherein j is
 0. 220. The compound of any one ofclaims 203 to 219, wherein k is
 0. 221. The compound of any one ofclaims 203 to 220, wherein the linker has the structure of

wherein x is 1, 2, 3, 4, 5, 6, 7, or 8; y is 1, 2, 3, or 4; R^(x) is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; R^(y) is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and W is O orNR^(w), wherein R^(w) is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₆ carbocyclyl.
 222. The compound of any one of claims 203 to 221,wherein the linker has the structure of:


223. The compound of any one of claims 203 to 221, wherein the linkerhas the structure of


224. The compound of any one of claims 2 to 202, wherein the linker hasthe structure of Formula V:A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)—(F³)_(o2)-(E²)_(p)-A²,  FormulaV wherein A¹ is a bond between the linker and A; A² is a bond between Band the linker; each of m, n, o1, o2, and p is, independently, 0 or 1;each of E¹ and E² is, independently, O, S, NR^(N), optionallysubstituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀ alkenylene,optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₁₀polyethylene glycol, or optionally substituted C₁₋₁₀ heteroalkylene; E³is optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆heteroalkylene, O, S, or NR^(N); each R^(N) is, independently, H,optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₂₋₆heterocyclyl, optionally substituted C₆₋₁₂ aryl, or optionallysubstituted C₁₋₇ heteroalkyl; C³ is carbonyl, thiocarbonyl, sulphonyl,or phosphoryl; and each of F¹, F², and F³ is, independently, optionallysubstituted C₃-C₁₀ carbocyclylene, optionally substituted C₂₋₁₀heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene.
 225. The compound of claim 224, whereinthe linker has the structure of Formula Va:A¹-(E¹)-(F¹)—(C³)_(m)-(E²)_(p)-A².  Formula Va
 226. The compound ofclaim 224, wherein the linker has the structure of Formula Vb:A¹-(E¹)-(F¹)-(E²)_(p)-A².  Formula Vb
 227. The compound of claim 224,wherein the linker has the structure of Formula Vc:A¹-(E¹)-(F¹)-A².  Formula Vc
 228. The compound of claim 224, wherein thelinker has the structure of Formula Vd:A¹-(E¹)-(F¹)—(C³)_(m)—(F²)_(o1)-A².  Formula Vd
 229. The compound ofclaim 224, wherein the linker has the structure of Formula Ve:A¹-(E¹)-(F¹)—(F²)_(o1)-A².  Formula Ve
 230. The compound of claim 224,wherein the linker has the structure of Formula Vf:A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A²,  Formula Vf
 231. The compound ofclaim 224, wherein the linker has the structure of Formula Vg:A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A²,  Formula Vg
 232. The compound of anyone of claims 224 to 231, wherein each of E¹ and E² is, independently,NR^(N), optionally substituted C₁₋₁₀ alkylene, optionally substitutedC₂-C₁₀ polyethylene glycolene, or optionally substituted C₁₋₁₀heteroalkylene.
 233. The compound of any one of claims 224 to 232,wherein E³ is optionally substituted C₁-C₆ alkylene, O, S, or NR^(N).234. The compound of claim 233, wherein E³ is optionally substitutedC₁-C₆ alkylene.
 235. The compound of claim 233, wherein E³ is optionallysubstituted C₁-C₃ alkylene.
 236. The compound of claim 233, wherein E³is

where a is 0, 1, 2, 3, 4, or
 5. 237. The compound of claim 233, whereinE³ is


238. The compound of claim 233, wherein E³ is O.
 239. The compound ofany one of claims 224 to 238, wherein each R^(N) is, independently, H oroptionally substituted C₁₋₄ alkyl.
 240. The compound of claim 239,wherein each R^(N) is, independently, H or methyl.
 241. The compound ofany one of claims 224 to 240, wherein E¹

where a is 0, 1, 2, 3, 4, or
 5. 242. The compound of claim 241, whereinE¹ is


243. The compound of claim 242, wherein E¹ is


244. The compound of any one of claims 224 to 243, wherein E¹ is

wherein b is 0, 1, 2, 3, 4, 5, or 6; R^(a) is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl; R^(b) is H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl; and R^(c) is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl.
 245. The compound of claim 244, whereinE¹ is


246. The compound of claim 245, wherein E¹ is


247. The compound of claim 246, wherein E¹ is


248. The compound of claim 247, wherein E¹ is


249. The compound of any one of claims 244 to 248, wherein R^(a) is H ormethyl.
 250. The compound of claim 249, wherein R^(a) is H.
 251. Thecompound of claim 249, wherein R^(a) is methyl.
 252. The compound of anyone of claims 224 to 251, wherein E² is O, NR^(w),

wherein c is 0, 1, 2, 3, 4, 5, 6, 7, or 8; d is 0, 1, 2, or 3; e is 0,1, 2, 3, 4, 5, or 6; f is 0, 1, 2, 3, or 4; R^(d) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(e) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(f) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(g) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; and W is O or NR^(w), whereinR^(w) is H or optionally substituted C₁-C₆ alkyl.
 253. The compound ofclaim 252, wherein E² is O,


254. The compound of any one of claims 224 to 253, wherein each of F¹,F², or F³ is, independently, optionally substituted C₃-C₁₀carbocyclylene.
 255. The compound of claim 254, wherein the C₃-C₁₀carbocyclylene is monocyclic.
 256. The compound of claim 254, whereinthe C₃-C₁₀ carbocyclylene is polycyclic.
 257. The compound of claim 256,wherein the C₃-C₁₀ carbocyclylene is fused.
 258. The compound of claim256, wherein the C₃-C₁₀ carbocyclylene is spirocyclic.
 259. The compoundof claim 256, wherein the C₃-C₁₀ carbocyclylene is bridged.
 260. Thecompound of claim 259, wherein the C₃-C₁₀ carbocyclylene is


261. The compound of claim 260, wherein the C₃-C₁₀ carbocyclylene is


262. The compound of any one of claims 224 to 253, wherein each of F¹,F², or F³ is, independently, optionally substituted C₂-C₆heterocyclylene.
 263. The compound of claim 262, wherein the C₂-C₆heterocyclylene is monocyclic.
 264. The compound of claim 263, whereinthe C₂-C₆ heterocyclylene is

wherein q1 is 0, 1, 2, 3, or 4; q2 is 0, 1, 2, 3, 4, 5, or 6; q3 is 0,1, 2, 3, 4, 5, 6, 7, or 8; each R^(h) is, independently, ²H, halogen,optionally substituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4); or twoR^(h) groups, together with the carbon atom to which each is attached,combine to form optionally substituted C₃-C₁₀ carbocyclyl or optionallysubstituted C₂-C₉ heterocyclyl; or two R^(h) groups, together with thecarbon atoms to which each is attached, combine to form optionallysubstituted C₃-C₁₀ carbocyclyl or optionally substituted C₂-C₉heterocyclyl; R^(i1) is H or optionally substituted C₁-C₆ alkyl; R^(i2)is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;
 265. Thecompound of claim 264, wherein the C₂-C₉ heterocyclylene is


266. The compound of claim 264 or 265, wherein each R^(h) is,independently, ²H, halogen, cyano, optionally substituted C₁-C₆ alkyl,OR^(i2), or NR^(i3)R^(i4).
 267. The compound of claim 266, wherein eachR^(h) is, independently, ²H, F, methyl


268. The compound of claim 267, wherein each R^(h) is, independently, F,methyl, or NR^(i3)R^(i4).
 269. The compound of any one of claims 264 to268, wherein q1 is 0, 1, or
 2. 270. The compound of any one of claims264 to 269, wherein q2 is 0, 1, or
 2. 271. The compound of any one ofclaims 264 to 270, wherein q3 is 0, 1, or
 2. 272. The compound of anyone of claims 264 to 271, wherein the C₂-C₉ heterocyclylene is


273. The compound of claim 272, wherein the C₂-C₉ heterocyclylene is


274. The compound of claim 273, wherein the C₂-C₉ heterocyclylene is


275. The compound of any one of claims 264 to 274, wherein F¹ is


276. The compound of any one of claims 264 to 275, wherein F² is


277. The compound of any one of claims 264 to 275, wherein F³ is


278. The compound of claim 262, wherein the C₂-C₆ heterocyclylene ispolycyclic.
 279. The compound of claim 278, wherein the C₂-C₆heterocyclylene is bicyclic.
 280. The compound of claim 278 or 279,wherein the C₂-C₆ heterocyclylene is bridged.
 281. The compound of claim280, wherein the C₂-C₆ heterocyclylene is


282. The compound of claim 278 or 279, wherein the C₂-C₆ heterocyclyleneis fused.
 283. The compound of claim 282, wherein the C₂-C₉heterocyclylene is


284. The compound of claim 283, wherein F¹ is


285. The compound of claim 283 or 284, wherein F² is


286. The compound of claim 278 or 279, wherein the C₂-C₆ heterocyclyleneis spirocyclic.
 287. The compound of claim 286, wherein the C₂-C₆heterocyclylene is


288. The compound of claim 287, wherein F¹ is


289. The compound of claim 287 or 288, wherein F² is


290. The compound of any one of claims 287 to 289, wherein F³ is


291. The compound of any one of claims 262 to 290 wherein the C₂-C₉heterocyclylene comprises a quaternary amine.
 292. The compound of anyone of claims 224 to 253, wherein each of F¹, F², or F³ is,independently, optionally substituted C₆-C₁₀ arylene.
 293. The compoundof claim 292, wherein the C₆-C₁₀ arylene is


294. The compound of any one of claims 224 to 253, wherein each of F¹,F², or F³ is, independently, optionally substituted C₂-C₉ heteroarylene.295. The compound of claim 294, wherein the C₂-C₉ heteroarylene is


296. The compound of claim 295, wherein F² is


297. The compound of claim 296, wherein F² is


298. The compound of any one of claims 224 to 297, C³ is


299. The compound of claim 298, wherein C³ is


300. The compound of any one of claims 224 to 299, wherein m is
 1. 301.The compound of any one of claims 224 to 299, wherein m is
 0. 302. Thecompound of any one of claims 224 to 301, wherein p is
 1. 303. Thecompound of any one of claims 224 to 301, wherein p is
 0. 304. Thecompound of any one of claims 224 to 303, wherein o1 is
 1. 305. Thecompound of any one of claims 224 to 303, wherein o1 is
 0. 306. Thecompound of any one of claims 224 to 305, wherein o2 is
 1. 307. Thecompound of any one of claims 224 to 305, wherein o2 is
 0. 308. Thecompound of any one of claims 224 to 307, wherein n is
 1. 309. Thecompound of any one of claims 224 to 307, wherein n is
 0. 310. Thecompound of any one of claims 224 to 309, wherein the linker has thestructure of


311. The compound of any one of claims 224 to 309, wherein the linkerhas the structure of


312. The compound of any one of claims 224 to 309, wherein the linkerhas the structure of:


313. The compound of any one of claims 2 to 202, wherein the linker isoptionally substituted C₃-C₁₀ carbocyclylene, optionally substitutedC₂₋₁₀ heterocyclylene, optionally substituted C₆-C₁₀ arylene, oroptionally substituted C₂-C₉ heteroarylene.
 314. The compound of claim313, wherein the linker is optionally substituted C₂₋₁₀ heterocyclylene315. The compound of claim 312, wherein the linker has the structure of


316. The compound of claim 315, wherein the linker has the structure of


317. The compound of any one of claims 2 to 202, wherein the linker isabsent.
 318. The compound of claim 1, wherein the compound has thestructure of any one of compounds B1-B6 in Table 1, or apharmaceutically acceptable salt thereof.
 319. The compound of any oneof claims 2 to 317, wherein the compound has the structure of any one ofcompounds D1-D31 in Table 2A, or a pharmaceutically acceptable saltthereof.
 320. The compound of any one of claims 2 to 317, wherein thecompound has the structure of any one of compounds D32-D184 in Table 2B,or a pharmaceutically acceptable salt thereof.
 321. The compound of anyone of claims 2 to 317, wherein the compound has the structure of anyone of compounds D185-D316 in Table 2C, or a pharmaceutically acceptablesalt thereof.
 322. A pharmaceutical composition comprising the compoundof any one of claims 1 to 321 and a pharmaceutically acceptableexcipient.
 323. A method of inhibiting the level of BRD9 in a cell, themethod involving contacting the cell with an effective amount of acompound of any one of claims 1 to 321, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 322. 324. Amethod of inhibiting the activity of BRD9 in a cell, the methodinvolving contacting the cell with an effective amount of a compound ofany one of claims 1 to 321, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of claim
 322. 325. The methodof claim 323 or 324, wherein the cell is a cancer cell.
 326. The methodof claim 325, wherein the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma,non-small cell lung cancer, stomach cancer, or breast cancer.
 327. Themethod of claim 326, wherein the cancer is a sarcoma.
 328. The method ofclaim 327, wherein the sarcoma is a soft tissue sarcoma, synovialsarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adultfibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cellsarcoma, desmoplastic small round cell tumor, epithelioid sarcoma,fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma,liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheralnerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.329. The method of claim 328, wherein the sarcoma is synovial sarcoma.330. A method of treating a BAF complex-related disorder in a subject inneed thereof, the method involving administering to the subject aneffective amount of a compound of any one of claims 1 to 321, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 322. 331. A method of treating an SS18-SSX fusionprotein-related disorder in a subject in need thereof, the methodinvolving administering to the subject an effective amount of a compoundof any one of claims 1 to 321, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of claim
 322. 332. A method oftreating a BRD9-related disorder in a subject in need thereof, themethod involving administering to the subject an effective amount of acompound of any one of claims 1 to 321, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 322. 333. Themethod of any one of claims 330 to 332, wherein the disorder is cancer.334. A method of treating a cancer in a subject in need thereof, themethod including administering to the subject an effective amount of acompound of any one of claims 1 to 321, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 322. 335. Themethod of claim 333 or 334, wherein the cancer is a malignant, rhabdoidtumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma,bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer,prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, asarcoma, non-small cell lung cancer, stomach cancer, or breast cancer.336. The method of claim 335, wherein the cancer is a sarcoma.
 337. Themethod of claim 336, wherein the sarcoma is a soft tissue sarcoma,synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adultfibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cellsarcoma, desmoplastic small round cell tumor, epithelioid sarcoma,fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma,liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheralnerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.338. The method of claim 337, wherein the sarcoma is synovial sarcoma.339. The method of any one of claims 330 to 332, wherein the disorder isinfection.
 340. A method of treating infection in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound of any one of claims 1 to 321, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 322. 341. The method of claim 339 or 340, whereinthe infection is viral infection.
 342. The method of claim 341, whereinthe viral infection is an infection with a virus of the Retroviridaefamily, Hepadnaviridae family, Flaviviridae family, Adenoviridae family,Herpesviridae family, Papillomaviridae family, Parvoviridae family,Polyomaviridae family, Paramyxoviridae family, or Togaviridae family.343. The method of claim 341 or 342, wherein the viral infection isCoffin Siris, Neurofibromatosis, or Multiple Meningioma.